Prodrugs of pyridone amides useful as modulators of sodium channels

ABSTRACT

The invention relates to prodrug compounds of formula I: 
                         
wherein R 2 , R 3 , R 5 , R 7  and X are as defined herein. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders, including pain. The compounds of formula I possess advantageous solubility and physicochemical properties.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/260,778, filed Sep. 9, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/858,635, filed Sep. 18, 2015, which is acontinuation of U.S. patent application Ser. No. 14/568,391, filed Dec.12, 2014, which claims the benefit of U.S. Provisional PatentApplication No. 61/915,937 filed Dec. 13, 2013, all of which areincorporated by reference in their entirety.

BACKGROUND OF THE APPLICATION

Pain is a protective mechanism that allows healthy animals to avoidtissue damage and to prevent further damage to injured tissue.Nonetheless there are many conditions where pain persists beyond itsusefulness, or where patients would benefit from inhibition of pain.Neuropathic pain is a form of chronic pain caused by an injury to thesensory nerves (Dieleman, J. P., et al., Incidence rates and treatmentof neuropathic pain conditions in the general population. Pain, 2008.137(3): p. 681-8). Neuropathic pain can be divided into two categories,pain caused by generalized metabolic damage to the nerve and pain causedby a discrete nerve injury. The metabolic neuropathies include postherpetic neuropathy, diabetic neuropathy, and drug-induced neuropathy.Discrete nerve injuries indications include post amputation pain,post-surgical nerve injury pain, and nerve entrapment injuries likeneuropathic back pain.

Voltage-gated sodium channels (Na_(V)'s) play a critical role in painsignaling. Na_(V)'s are key biological mediators of electrical signalingas they are the primary mediators of the rapid upstroke of the actionpotential of many excitable cell types (e.g. neurons, skeletal myocytes,cardiac myocytes). The evidence for the role of these channels in normalphysiology, the pathological states arising from mutations in sodiumchannel genes, preclinical work in animal models, and the clinicalpharmacology of known sodium channel modulating agents all point to thecentral role of Na_(V)'s in pain sensation (Rush, A. M. and T. R.Cummins, Painful Research: Identification of a Small-Molecule Inhibitorthat Selectively Targets Na _(V)1.8 Sodium Channels. Mol Interv, 2007.7(4): p. 192-5); England, S., Voltage-gated sodium channels: the searchfor subtype-selective analgesics. Expert Opin Investig Drugs 17 (12), p.1849-64 (2008); Krafte, D. S. and Bannon, A. W., Sodium channels andnociception: recent concepts and therapeutic opportunities. Curr OpinPharmacol 8 (1), p. 50-56 (2008)). Na_(V)'s are the primary mediators ofthe rapid upstroke of the action potential of many excitable cell types(e.g. neurons, skeletal myocytes, cardiac myocytes), and thus arecritical for the initiation of signaling in those cells (Hille, Bertil,Ion Channels of Excitable Membranes, Third ed. (Sinauer Associates,Inc., Sunderland, Mass., 2001)). Because of the role Na_(V)'s play inthe initiation and propagation of neuronal signals, antagonists thatreduce Na_(V) currents can prevent or reduce neural signaling and Na_(V)channels have long been considered likely targets to reduce pain inconditions where hyper-excitability is observed (Chahine, M., Chatelier,A., Babich, O., and Krupp, J. J., Voltage-gated sodium channels inneurological disorders. CNS Neurol Disord Drug Targets 7 (2), p. 144-58(2008)). Several clinically useful analgesics have been identified asinhibitors of Na_(V) channels. The local anesthetic drugs such aslidocaine block pain by inhibiting Na_(V) channels, and other compounds,such as carbamazepine, lamotrigine, and tricyclic antidepressants thathave proven effective at reducing pain have also been suggested to actby sodium channel inhibition (Soderpalm, B., Anticonvulsants: aspects oftheir mechanisms of action. Eur J Pain 6 Suppl A, p. 3-9 (2002); Wang,G. K., Mitchell, J., and Wang, S. Y., Block of persistent late Na⁺currents by antidepressant sertraline and paroxetine. J Membr Biol 222(2), p. 79-90 (2008)).

The Na_(V)'s form a subfamily of the voltage-gated ion channelsuper-family and comprises 9 isoforms, designated Na_(V)1.1-Na_(V)1.9.The tissue localizations of the nine isoforms vary greatly. Na_(V)1.4 isthe primary sodium channel of skeletal muscle, and Na_(V)1.5 is primarysodium channel of cardiac myocytes. Na_(V)'s 1.7, 1.8 and 1.9 areprimarily localized to the peripheral nervous system, while Na_(V)'s1.1, 1.2, 1.3, and 1.6 are neuronal channels found in both the centraland peripheral nervous systems. The functional behaviors of the nineisoforms are similar but distinct in the specifics of theirvoltage-dependent and kinetic behavior (Catterall, W. A., Goldin, A. L.,and Waxman, S. G., International Union of Pharmacology. XLVII.Nomenclature and structure-function relationships of voltage-gatedsodium channels. Pharmacol Rev 57 (4), p. 397 (2005)).

Immediately upon their discovery, Na_(V)1.8 channels were identified aslikely targets for analgesia (Akopian, A. N., L. Sivilotti, and J. N.Wood, A tetrodotoxin-resistant voltage-gated sodium channel expressed bysensory neurons. Nature, 1996. 379(6562): p. 257-62). Since then,Na_(V)1.8 has been shown to be the most significant carrier of thesodium current that maintains action potential firing in small DRGneurons (Blair, N. T. and B. P. Bean, Roles of tetrodotoxin(TTX)-sensitive Na+ current, TTX-resistant Na⁺ current, and Ca²⁺ currentin the action potentials of nociceptive sensory neurons. J Neurosci.,2002. 22(23): p. 10277-90). Na_(V)1.8 is essential for spontaneousfiring in damaged neurons, like those that drive neuropathic pain (Roza,C., et al., The tetrodotoxin-resistant Na⁺ channel Na_(V)1.8 isessential for the expression of spontaneous activity in damaged sensoryaxons of mice. J. Physiol., 2003. 550(Pt 3): p. 921-6; Jarvis, M. F., etal., A-803467, a potent and selective Na_(V)1.8 sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat. Proc Natl AcadSci. USA, 2007. 104(20): p. 8520-5; Joshi, S. K., et al., Involvement ofthe TTX-resistant sodium channel NaV1.8 in inflammatory and neuropathic,but not post-operative, pain states. Pain, 2006. 123(1-2): pp. 75-82;Lai, J., et al., Inhibition of neuropathic pain by decreased expressionof the tetrodotoxin-resistant sodium channel, Na_(V)1.8. Pain, 2002.95(1-2): p. 143-52; Dong, X. W., et al., Small interfering RNA-mediatedselective knockdown of Na(_(V))1.8 tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats. Neuroscience, 2007.146(2): p. 812-21; Huang, H. L., et al., Proteomic profiling of neuromasreveals alterations in protein composition and local protein synthesisin hyper-excitable nerves. Mol Pain, 2008. 4: p. 33; Black, J. A., etal., Multiple sodium channel isoforms and mitogen-activated proteinkinases are present in painful human neuromas. Ann Neurol, 2008. 64(6):p. 644-53; Coward, K., et al., Immunolocalization of SNS/PN3 andNaN/SNS2 sodium channels in human pain states. Pain, 2000. 85(1-2): p.41-50; Yiangou, Y., et al., SNS/PN3 and SNS2/NaN sodium channel-likeimmunoreactivity in human adult and neonate injured sensory nerves. FEBSLett, 2000. 467(2-3): p. 249-52; Ruangsri, S., et al., Relationship ofaxonal voltage-gated sodium channel 1.8 (Na_(V)1.8) mRNA accumulation tosciatic nerve injury-induced painful neuropathy in rats. J Biol Chem.286(46): p. 39836-47). The small DRG neurons where Na_(V)1.8 isexpressed include the nociceptors critical for pain signaling. Na_(V)1.8is the primary channel that mediates large amplitude action potentialsin small neurons of the dorsal root ganglia (Blair, N. T. and B. P.Bean, Roles of tetrodotoxin (TTX)-sensitive Na⁺ current, TTX-resistantNa⁺ current, and Ca²⁺ current in the action potentials of nociceptivesensory neurons. J Neurosci., 2002. 22(23): p. 10277-90). Na_(V)1.8 isnecessary for rapid repetitive action potentials in nociceptors, and forspontaneous activity of damaged neurons. (Choi, J. S. and S. G. Waxman,Physiological interactions between Na_(V)1.7 and Na_(V)1.8 sodiumchannels: a computer simulation study. J Neurophysiol. 106(6): p.3173-84; Renganathan, M., T. R. Cummins, and S. G. Waxman, Contributionof Na(_(v))1.8 sodium channels to action potential electrogenesis in DRGneurons. J Neurophysiol., 2001. 86(2): p. 629-40; Roza, C., et al., Thetetrodotoxin-resistant Na⁺ channel Na_(V)1.8 is essential for theexpression of spontaneous activity in damaged sensory axons of mice. JPhysiol., 2003. 550(Pt 3): p. 921-6). In depolarized or damaged DRGneurons, Na_(V)1.8 appears to be the primary driver ofhyper-excitablility (Rush, A. M., et al., A single sodium channelmutation produces hyper- or hypoexcitability in different types ofneurons. Proc Natl Acad Sci USA, 2006. 103(21): p. 8245-50). In someanimal pain models, Na_(V)1.8 mRNA expression levels have been shown toincrease in the DRG (Sun, W., et al., Reduced conduction failure of themain axon of polymodal nociceptive C-fibres contributes to painfuldiabetic neuropathy in rats. Brain. 135(Pt 2): p. 359-75; Strickland, I.T., et al., Changes in the expression of NaV1.7, Na_(V)1.8 and Na_(V)1.9in a distinct population of dorsal root ganglia innervating the rat kneejoint in a model of chronic inflammatory joint pain. Eur J Pain, 2008.12(5): p. 564-72; Qiu, F., et al., Increased expression oftetrodotoxin-resistant sodium channels Na_(V)1.8 and Na_(V)1.9 withindorsal root ganglia in a rat model of bone cancer pain. Neurosci. Lett.512(2): p. 61-6).

The primary drawback to the known Na_(V) inhibitors is their poortherapeutic window, and this is likely a consequence of their lack ofisoform selectivity. Since Na_(V)1.8 is primarily restricted to theneurons that sense pain, selective Na_(V)1.8 blockers are unlikely toinduce the adverse events common to non-selective Na_(V) blockers.Accordingly, there remains a need to develop additional Na_(V) channelantagonists preferably those that are more NaV1.8 selective and morepotent with increased metabolic stability, increased solubility and withfewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable salts and compositions thereof, are usefulas inhibitors of voltage-gated sodium channels. These compounds have thegeneral formula I:

wherein, independently for each occurrence:

-   R² and R³ are independently hydrogen, halogen, or C₁-C₆ alkyl    wherein said C₁-C₆ alkyl is substituted with 0-6 halogen;-   R⁵ is hydrogen, halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl    is substituted with 0-6 halogen and wherein up to two non-adjacent    CH₂ units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is hydrogen, halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation; provided that R², R³,    R⁵, and R⁷ are not simultaneously hydrogen.

The present invention also relates to novel, solid forms of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate (‘compound 9”). In one embodiment, the presentinvention provides solid Form B of compound 9, which is characterized byan X-ray powder diffraction (XRPD) comprising at least three approximatepeak positions (degrees 2 theta [2θ]±0.2) when measured using Cu K_(α)radiation, selected from the group consisting of 4.4, 12.7, 13.3, 14.7,15.2, 16.4, 18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2,24.8, 26.3, 29.6, 30.1 and 31.3, when the XPRD is collected from about 4to about 40 degrees two theta (2θ). Solid Form B may also becharacterized by an X-ray powder diffraction pattern, as measured usingCu K_(α) radiation, substantially similar to FIG. 2 and an endothermicpeak having an onset temperature at about 210° C. as measured bydifferential scanning calorimetry in which the temperature is scanned atabout 10° C. per minute. The present application also provides a methodfor preparing crystal Form B of compound 9 by suspending a solidmaterial of free compound 9 in a solvent system comprising water, anorganic solvent or an organic solvent/water mixture and isolating thesolid. In another embodiment, the present invention provides amorphousForm C of compound 9, which is characterized by an X-ray powderdiffraction (XRPD) substantially similar to that in FIG. 5. In anotherembodiment, the present invention provides a spray dry dispersion ofamorphous Form C of compound 9, which is characterized by an X-raypowder diffraction (XRPD) substantially similar to that in FIG. 6.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutically acceptable compositions comprising acompound of formula I and a pharmaceutically acceptable carrier,adjuvant, or vehicle.

In another embodiment, the present invention relates to a pharmaceuticalcomposition comprising a compound of formula I; a pharmaceuticallyacceptable carrier, adjuvant, or vehicle; and an additional therapeuticagent.

In another embodiment, the present invention relates to a method oftreating or lessening the severity of a variety of diseases, disorders,or conditions in a subject, including, but not limited to, chronic pain,gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia comprising administering to the subject atherapeutically effective amount of a compound of formula I.

In another embodiment, the present invention relates to a method oftreating or lessening the severity of a variety of diseases, disorders,or conditions in a subject, including, but not limited to, chronic pain,gut pain, neuropathic pain, musculoskeletal pain, acute pain,inflammatory pain, cancer pain, idiopathic pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia comprising administering to the subject atherapeutically effective amount of a compound of formula I and anadditional therapeutic agent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a thermal ellipsoid plot of one symmetry independent moleculeof crystalline Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

FIG. 2 shows an X-ray powder diffraction pattern of solid Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

FIG. 3 shows a DSC (DifferentialScanning calorimetry) thermogram ofsolid Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

FIG. 4 shows a TGA (thermal gravimetric analysis) thermogram of solidForm B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

FIG. 5 shows an X-ray powder diffraction pattern of solid neat amorphousForm C of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

FIG. 6 shows an X-ray powder diffraction pattern of amorphous Form Cfrom a spray dry dispersion of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

DETAILED DESCRIPTION OF THE INVENTION

The instant compounds of formula I are prodrugs of their respectiveparent compounds. Thus, the activity exhibited upon administration ofthe prodrug is principally due to the presence of the parent compoundthat results from cleavage of the prodrug.

The present invention also relates to novel, solid forms of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate (“compound 9”). In one embodiment,the present invention provides a free crystalline form of compound 9(Form B). In another embodiment, the present invention provides aprocess for preparing solid Form B of compound 9. In another embodiment,the present invention provides an amorphous form of compound 9 (Form C).In yet another embodiment, the present invention provides a method ofpreparing amorphous Form C of compound 9.

The term “prodrug” refers to compounds which are drug precursors which,following administration and absorption, release the drug in vivo viasome metabolic process. In general, a prodrug possesses less biologicalactivity than its parent drug. A prodrug may also improve the physicalproperties of the parent drug and/or it may also improve overall drugefficacy, for example through the reduction of toxicity and unwantedeffects of a drug by controlling its absorption, blood levels, metabolicdistribution and cellular uptake.

The term “parent compound” or “parent drug” refers to the biologicallyactive entity that is released via enzymatic action of a metabolic or acatabolic process, or via a chemical process following administration ofthe prodrug. The parent compound may also be the starting material forthe preparation of its corresponding prodrug.

The monovalent cations defined by M⁺ include ammonium (e.g., N(R⁹)₄,wherein R⁹ is H or C₁-C₄ alkyl), alkali metal ions such as sodium,lithium and potassium ions, dicyclohexylamine ion, andN-methyl-D-glucamine ion. The divalent cations defined by D²⁺include-alkaline earth metal ions such as calcium and magnesium ions, aswell as divalent aluminum ions. Also included are amino acid cationssuch as monovalent or divalent ions of arginine, lysine, ornithine, andso forth. If M⁺ is a monovalent cation, it is recognized that if thedefinition 2M⁺ is present, each of M⁺ may be the same or different. Inaddition, it is similarly recognized that if the definition 2M⁺ ispresent, a divalent cation D²⁺ may instead be present. Also, the basicnitrogen-containing groups may be quaternized with such agents as: loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl;diamyl sulfates; long chain halides such as decyl, lauryl, myristyl andstearyl chlorides, bromides and iodides; aralkyl halides like benzylbromide and others.

The prodrugs and solid forms of the present invention are characterizedby unexpectedly high aqueous solubility. This solubility facilitatesadministration of higher doses of the prodrug, resulting in a greaterdrug load per unit dosage.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry,”Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry,” 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As one of ordinary skill in the art will recognize, combinations ofsubstituents envisioned by this invention are those combinations thatresult in the formation of stable or chemically feasible compounds. Theterm “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and preferably their recovery, purification, anduse for one or more of the purposes disclosed herein. In someembodiments, a stable compound or chemically feasible compound is onethat is not substantially altered when kept at a temperature of 40° C.or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The term “alkyl” as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chainthat is completely saturated or that contains one or more units ofunsaturation. Suitable alkyl groups include, but are not limited to,linear or branched, and substituted or unsubstituted alkyl.

The term “halogen” or “halo” as used herein, means F, Cl, Br or I.

The phrase “up to,” as used herein, refers to zero or any integer numberthat is equal or less than the number following the phrase. For example,“up to 4” means any one of 0, 1, 2, 3, and 4.

Within a definition of a term as, for example, 127 when a CH₂ unit or,interchangeably, methylene unit may be replaced by —O—, it is meant toinclude any CH₂ unit, including a CH₂ within a terminal methyl group.For example, CH₂CH₂CH₂OH is within the definition of C₁-C₆ alkyl whereinup to two non-adjacent CH₂ units may be replaced by —O— because the CH₂unit of the terminal methyl group has been replaced by —O—.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Thus, included within the scope of the invention aretautomers of compounds of formula I. The structures also includezwitterioinc forms of the compounds or salts of formula whereappropriate.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched or isotopically-labeled atoms. Theisotopically-labeled compounds may have one or more atoms replaced by anatom having an atomic mass or mass number usually found in nature.Examples of isotopes present in compounds of formula I include isotopesof hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³⁵S and ¹⁸F. Certain isotopically-labeled compounds of formula I, inaddition to being useful as therapeutic agents, are also useful in drugand/or substrate tissue distribution assays, as analytical tools or asprobes in other biological assays. In one aspect of the presentinvention, tritiated (e.g., ³H) and carbon-14 (e.g., ¹⁴C) isotopes areuseful given their ease of detectability. In another aspect of thepresent invention, replacement of one or more hydrogen atoms withheavier isotopes such as deuterium, (e.g., ²H) can afford certaintherapeutic advantages.

In one embodiment, the invention features a compound of formula I andthe attendant definitions, wherein R² is H. In another embodiment, R² ishalogen. In another embodiment, R² is Cl. In another embodiment, R² isF. In another embodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen. In another embodiment, R² is CF₃. Inanother embodiment, R² is H, Cl or CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is H. In another embodiment,R³ is halogen. In another embodiment, R³ is Cl. In another embodiment,R³ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6halogen. In another embodiment, R³ is CF₃. In another embodiment, R³ isCF₂CF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁵ is H. In another embodiment,R⁵ is halogen. In another embodiment, R⁵ is Cl. In another embodiment,R⁵ is F. In another embodiment, R⁵ is C₁-C₆ alkyl. In anotherembodiment, R⁵ is CH₃. In another embodiment, R⁵ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein one CH₂ unit ofsaid C₁-C₆ alkyl is replaced with —O—. In another embodiment, R⁵ isOCH₃. In another embodiment, R⁵ is OH. In another embodiment, R⁵ isOCF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R⁷ is H. In another embodiment,R⁷ is halogen. In another embodiment, R⁷ is F. In another embodiment, R⁷is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substituted with 0-6 halogenwherein two non-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with—O—. In another embodiment, R⁷ is OCH₃. In another embodiment, R⁷ isOCF₃.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group. In another embodiment, the inventionfeatures a compound of formula I and the attendant definitions, whereinX is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺. In one embodiment, X is PO(O⁻)₂.2M⁺ andM⁺ is Na⁺. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. Inanother embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein eachR⁹ is independently H or a C₁-C₄ alkyl group. In another embodiment, Xis —PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(O⁻)₂.2M⁺, M^(t) is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ whereineach R⁹ is independently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ whereineach R⁹ is independently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺.In yet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺.In yet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁷ is F, X is—PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. Inyet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula Iand the attendant definitions, wherein R² is CF₃, R⁷ is F, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention provides a compound of formula I-A

wherein, independently for each occurrence:

-   R² is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen;-   R⁵ is halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl. In another embodiment, R² is F. In anotherembodiment, R² is C₁-C₆ alkyl wherein said C₁-C₆ alkyl is substitutedwith 0-6 halogen. In another embodiment, R² is CF₃. In anotherembodiment, R² is Cl or CF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. Inanother embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃. In anotherembodiment, R⁵ is F, Cl, CH₃, OCH₃, OH or OCF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein twonon-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with —O—. Inanother embodiment, R⁷ is OCH₃. In another embodiment, R⁷ is OCF₃. Inanother embodiment, R⁷ is F, OCH₃ or OCF₃.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is CF₃, R⁵ is Cl, OCH₃ or CH₃and R⁷ is F. In one embodiment, R² is CF₃, R⁵ is Cl and R⁷ is F. Inanother embodiment, R² is CF₃, R⁵ is OCH₃ and R⁷ is F. In anotherembodiment, R² is CF₃, R⁵ is CH₃ and R⁷ is F.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is CF₃, R⁵ is Cl, OCH₃ or CH₃,R⁷ is F and X is —PO(OH)₂. In one embodiment, R² is CF₃, R⁵ is Cl, R⁷ isF and X is —PO(OH)₂. In another embodiment, R² is CF₃, R⁵ is OCH₃, R⁷ isF and X is —PO(OH)₂. In another embodiment, R² is CF₃, R⁵ is CH₃, R⁷ isF and X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺.In yet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula I-Aand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention provides a compound of formula I-B

wherein, independently for each occurrence:

-   R³ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen;-   R⁵ is halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl. In another embodiment, R³ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment,R³ is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. Inanother embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R⁷ is halogen. In anotherembodiment, R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl whereinsaid C₁-C₆ alkyl is substituted with 0-6 halogen wherein twonon-adjacent CH₂ units of said C₁-C₆ alkyl are replaced with —O—. Inanother embodiment, R⁷ is OCH₃. In another embodiment, R⁷ is OCF₃.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₃, R⁵ is F or CH₃ and R⁷is F. In one embodiment, R³ is Cl, R⁵ is CH₃ and R⁷ is F. In anotherembodiment, R³ is CF₂CF₃, R⁵ is OCH₃ and R⁷ is F.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₃, R⁵ is F or CH₃, R⁷ isF and X is —PO(OH)₂. In one embodiment, R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂. In another embodiment, R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and is Mg⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻) 2.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₂CF₃, R⁵ is OCH₃, R⁷ is Fand X is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺.In yet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is CF₃, R⁵ is CH₃, R⁷ is F, Xis —PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula I-Band the attendant definitions, wherein R³ is Cl, R⁵ is CH₃, R⁷ is F andX is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ wherein each R⁹ isindependently H or a C₁-C₄ alkyl group.

In another embodiment, the invention provides a compound of formula I-C

wherein, independently for each occurrence:

-   R² is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment, R²is CF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R⁷ is halogen. In one embodiment,R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—. In oneembodiment, R⁷ is OCF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is CF₃ and R⁷ is F or OCF₃.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is CF₃, R⁷ is F or OCF₃ and Xis —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is CF₃, R⁵ is CH₃, R⁷ is F andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is CF₃, R⁷ is F, X is—PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺. In another embodiment, M⁺ is Li⁺. Inyet another embodiment, M⁺ is Na⁺.

In another embodiment, the invention features a compound of formula I-Cand the attendant definitions, wherein R² is CF₃, R⁷ is F, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is—PO(O⁻)₂.D²⁺ and D²⁺ is Mg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺and D²⁺ is Ca²⁺.

In another embodiment, the invention provides a compound of formula I-D

wherein, independently for each occurrence:

-   R³ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R³ is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment, R³is CF₃. In another embodiment, R³ is CF₂CF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R⁷ is halogen. In one embodiment,R⁷ is F. In another embodiment, R⁷ is C₁-C₆ alkyl wherein said C₁-C₆alkyl is substituted with 0-6 halogen and wherein up to two non-adjacentCH₂ units of said C₁-C₆ alkyl may be replaced with —O—. In oneembodiment, R⁷ is OCF₃.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R³ is CF₃ and R⁷ is CF₃. Inanother embodiment, R³ is CF₂CF₃ and R⁷ is F.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein R³ is CF₃, R⁷ is CF₃ and X is—PO(OH)₂. In another embodiment, R³ is CF₂CF₃, R⁷ is F and X is—PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and is Mg⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻) 2.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Dand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention provides a compound of formula I-E

wherein, independently for each occurrence:

-   R² and R³ are independently halogen, or C₁-C₆ alkyl wherein said    C₁-C₆ alkyl is substituted with 0-6 halogen;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R⁷ is halogen. In one embodiment,R⁷ is F.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R² and R³ are Cl and R⁷ is F.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein R² and R³ are Cl, R⁷ is F and Xis —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D⁺ is Mg⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻) 2.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D⁺ is Mg²⁺.In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. In anotherembodiment, X is —PO(O⁻)₂.D²⁺ and D⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Eand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention provides a compound of formula I-F

wherein, independently for each occurrence:

-   R² is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen;-   R⁵ is halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R² is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen. In another embodiment, R²is CF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R⁵ is C₁-C₆ alkyl wherein saidC₁-C₆ alkyl is substituted with 0-6 halogen and wherein up to twonon-adjacent CH₂ units of said C₁-C₆ alkyl may be replaced with —O—. Inone embodiment, R⁵ is CH₃. In another embodiment, R⁵ is OCF₃.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein R² is CF₃, R⁷ is CH₃ or OCF₃ andX is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D²⁺ is Mg²⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Fand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention provides a compound of formula I-G

wherein, independently for each occurrence:

-   R² and R³ are independently halogen, or C₁-C₆ alkyl wherein said    C₁-C₆ alkyl is substituted with 0-6 halogen;-   R⁵ is halogen, OH, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—;-   R⁷ is halogen, or C₁-C₆ alkyl wherein said C₁-C₆ alkyl is    substituted with 0-6 halogen and wherein up to two non-adjacent CH₂    units of said C₁-C₆ alkyl may be replaced with —O—; and    X is —PO(OH)₂, —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺, or —PO(O⁻)₂.D²⁺; M⁺ is a    pharmaceutically acceptable monovalent cation; and D²⁺ is a    pharmaceutically acceptable divalent cation.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² is halogen. In anotherembodiment, R² is Cl.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R³ is halogen. In anotherembodiment, R³ is Cl.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R⁵ is halogen. In anotherembodiment, R⁵ is Cl. In another embodiment, R⁵ is F. In anotherembodiment, R⁵ is C₁-C₆ alkyl. In another embodiment, R⁵ is CH₃. Inanother embodiment, R⁵ is C₁-C₆ alkyl wherein said C₁-C₆ alkyl issubstituted with 0-6 halogen wherein one CH₂ unit of said C₁-C₆ alkyl isreplaced with —O—. In another embodiment, R⁵ is OCH₃. In anotherembodiment, R⁵ is OH. In another embodiment, R⁵ is OCF₃.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R⁷ is halogen. In one embodiment,R⁷ is F.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(OH)₂, —PO(OH)O⁻M⁺;PO(O⁻)₂.2M⁺ or —PO(O⁻)₂.D²⁺; wherein M⁺ is Li⁺, Na⁺ or K⁺ and whereinD²⁺ is Mg²⁺ or Ca²⁺.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² and R³ are Cl, R⁵ is OCH₃ andR⁷ is F.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² and R³ are Cl, R⁷ is F, R⁵ isOCH₃ and X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(OH)O⁻M⁺, —PO(O⁻)₂.2M⁺;or —PO(O⁻)₂.D²⁺; M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺; wherein each R⁹ isindependently H or a C₁-C₄ alkyl group and D⁺ is Mg⁺, Ca²⁺ or Ba²⁺.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(OH)O⁻M⁺ and M⁺ is Li⁺.In one embodiment, X is PO(OH)O⁻M⁺ and M⁺ is Na⁺. In another embodiment,X is —PO(OH)O⁻M⁺ and M⁺ is K⁺. In another embodiment, X is —PO(OH)O⁻M⁺and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or a C₁-C₄ alkylgroup. In another embodiment, X is —PO(OH)O⁻M⁺ and M⁺ is N(R⁹)₄ ⁺;wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(O⁻)₂.2M⁺ and M⁺ is Li⁺.In one embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is Na⁺. In anotherembodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ is K⁺. In another embodiment, X is—PO(O⁻)₂.2M⁺ and M⁺ is N(R⁹)₄ ⁺; wherein each R⁹ is independently H or aC₁-C₄ alkyl group. In another embodiment, X is —PO(O⁻)₂.2M⁺ and M⁺ isN(R⁹)₄ ⁺; wherein each R⁹ is a CH₃ group.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺, Ca²⁺ or Ba²⁺. In one embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ isMg²⁺. In another embodiment, X is —PO(O⁻)₂.D²⁺ and D²⁺ is Ca²⁺. Inanother embodiment, X is —PO(O⁻)₂.D²⁺ and is Ba²⁺.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(OH)₂.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(O⁻)₂.2M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ whereineach R⁹ is independently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a compound of formula I-Gand the attendant definitions, wherein R² is Cl, R³ is Cl, R⁵ is OCH₃,R⁷ is F and X is —PO(OH)O⁻M⁺, M⁺ is Li⁺, Na⁺, K⁺ or N(R⁹)₄ ⁺ whereineach R⁹ is independently H or a C₁-C₄ alkyl group.

In another embodiment, the invention features a solid form of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

In one embodiment, the present invention provides a free crystallineForm B of compound 9.

In one embodiment, the present invention provides a crystalline Form Bof(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate.

In another embodiment, the present invention provides a crystalline FormB of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate which is characterized by an X-ray powderdiffraction pattern (XRPD) comprising at least three approximate peakpositions (degrees 2 theta±0.2) when measured using Cu K_(a) radiation,selected from the group consisting of 4.4, 15.2, 16.4, 18.0, 19.1, 19.3,19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3, 29.6, 30.1 and31.3, when the XRPD is collected from about 4 to about 40 degrees 2theta (2θ).

In another embodiment, the present invention provides a crystalline FormB of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate which is characterized by an X-ray powderdiffraction pattern (XRPD) comprising at least three approximate peakpositions (degrees 2 theta±0.2) when measured using Cu K_(a) radiation,selected from the group consisting of 19.3, 22.2, 23.5, 26.3 and 30.1,when the XRPD is collected from about 4 to about 40 degrees 2 theta(2θ).

In another embodiment, the present invention provides a crystalline FormB of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate characterized by an X-ray powder diffractionpattern, as measured by Cu K_(a) radiation, substantially similar toFIG. 2.

In another embodiment, the present invention provides a crystalline FormB of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate, further characterized by an endothermic peakhaving an onset temperature at about 210° C. degrees as measured bydifferential scanning calorimetry in which the temperature is scanned atabout 10° C. per minute.

In another embodiment, the present invention provides a process forpreparing solid Form B of compound 9.

In another embodiment, the present invention provides a process forpreparing crystalline Form B of compound 9.

In one embodiment of the process, a substantially pure solid Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 bycontacting the compound with an organic solvent, a mixture of organicsolvents or a mixture of an organic solvent and water at a suitabletemperature, stirring for up to 4 weeks and isolating the solid.

In another embodiment of the process, a substantially pure solid Form Bof compound 9 may be prepared from amorphous or crystalline compound 9by contacting the compound with water at a suitable temperature,stirring for up to 4 weeks and isolating the solid.

In another embodiment of the process, a substantially pure solid Form Bof compound 9 may be prepared from amorphous or crystalline compound 9by contacting the compound with an alcoholic solvent at roomtemperature, stirring for up to 4 weeks and isolating the solid. Inanother embodiment, the alcoholic solvent comprises methanol, ethanol orisopropanol.

In another embodiment of the process, a substantially pure solid Form Bof compound 9 may be prepared from amorphous or crystalline compound 9by contacting the compound with an organic ester solvent at roomtemperature, stirring for up to 4 weeks and isolating the solid. In oneembodiment, the organic ester solvent comprises ethyl acetate orisopropyl acetate.

In another embodiment of the process, a substantially pure solid Form Bof compound 9 may be prepared from amorphous or crystalline compound 9by contacting the compound with an organic solvent at room temperature,stirring for up to 4 weeks and isolating the solid. In one embodiment,the organic solvent comprises acetonitrile, acetone, tetrahydrofuran(THF), 2-methyl tetrahydrofuran or methyl ethyl ketone.

In another embodiment, a substantially pure solid Form B of compound 9may be prepared from amorphous or crystalline compound 9 by contactingthe compound with a mixture of an organic solvent and water at roomtemperature, stirring for up to 4 weeks and isolating the solid. In oneembodiment, the organic solvent/water mixture comprises THF/water,acetone/water or alcohol/water. In one embodiment, the alcohol of thealcohol/water mixture comprises, methanol, ethanol or isopropanol.

In another embodiment, a substantially pure solid Form B of compound 9may be prepared from amorphous or crystalline compound 9 by contactingthe compound with a mixture of an organic solvent and water at roomtemperature, stirring for up to 4 weeks and isolating the solid.

In another embodiment, a substantially pure solid Form B of compound 9may be prepared from amorphous or crystalline compound 9 by contactingthe compound with a mixture of an organic solvent and water at elevatedtemperature, stirring for up to 4 weeks and isolating the solid. Inanother embodiment, a substantially pure solid Form B of compound 9 maybe prepared from amorphous or crystalline compound 9 by contacting thecompound with a mixture of an organic solvent and water at reflux,stirring for up to 24 hours and isolating the solid. In one embodiment,the organic solvent/water mixture comprises THF/water, acetone/water oralcohol/water. In one embodiment, the organic solvent/water mixturecomprises acetone/water. In another embodiment, the organicsolvent/water mixture comprises THF/water.

In another embodiment, a substantially pure solid Form B of compound 9may be prepared from amorphous or crystalline compound 9 by exposing thecompound to atmospheric conditions for up to 4 weeks and isolating thesolid.

In one embodiment of the process, a substantially pure crystalline FormB of compound 9 may be prepared from amorphous or crystalline compound 9by contacting the compound with an organic solvent, a mixture of organicsolvents or a mixture of an organic solvent and water at a suitabletemperature, stirring for up to 4 weeks and isolating the crystallinesolid.

In another embodiment of the process, a substantially pure crystallineForm B of compound 9 may be prepared from amorphous or crystallinecompound 9 by contacting the compound with water at a suitabletemperature, stirring for up to 4 weeks and isolating the crystallinesolid.

In another embodiment of the process, a substantially pure crystallineForm B of compound 9 may be prepared from amorphous or crystallinecompound 9 by contacting the compound with an alcoholic solvent at roomtemperature, stirring for up to 4 weeks and isolating the crystallinesolid. In another embodiment, the alcoholic solvent comprises methanol,ethanol or isopropanol.

In another embodiment of the process, a substantially pure crystallineForm B of compound 9 may be prepared from amorphous or crystallinecompound 9 by contacting the compound with an organic ester solvent atroom temperature, stirring for up to 4 weeks and isolating thecrystalline solid. In one embodiment, the organic ester solventcomprises ethyl acetate or isopropyl acetate.

In another embodiment of the process, a substantially pure crystallineForm B of compound 9 may be prepared from amorphous or crystallinecompound 9 by contacting the compound with an organic solvent at roomtemperature, stirring for up to 4 weeks and isolating the crystallinesolid. In one embodiment, the organic solvent comprises acetonitrile,acetone, tetrahydrofuran (THF), 2-methyl tetrahydrofuran or methyl ethylketone.

In another embodiment, a substantially pure crystalline Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 bycontacting the compound with a mixture of an organic solvent and waterat room temperature, stirring for up to 4 weeks and isolating thecrystalline solid. In one embodiment, the organic solvent/water mixturecomprises THF/water, acetone/water or alcohol/water. In one embodiment,the alcohol of the alcohol/water mixture comprises, methanol, ethanol orisopropanol.

In another embodiment, a substantially pure crystalline Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 bycontacting the compound with a mixture of an organic solvent and waterat room temperature, stirring for up to 4 weeks and isolating thecrystalline solid.

In another embodiment, a substantially pure crystalline Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 bycontacting the compound with a mixture of an organic solvent and waterat elevated temperature, stirring for up to 4 weeks and isolating thesolid. In another embodiment, a substantially pure crystalline Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 bycontacting the compound with a mixture of an organic solvent and waterat reflux, stirring for up to 24 hours and isolating the crystallinesolid. In one embodiment, the organic solvent/water mixture comprisesTHF/water, acetone/water or alcohol/water. In one embodiment, theorganic solvent/water mixture comprises acetone/water. In anotherembodiment, the organic solvent/water mixture comprises THF/water.

In another embodiment, a substantially pure crystalline Form B ofcompound 9 may be prepared from amorphous or crystalline compound 9 byexposing the compound to atmospheric conditions for up to 4 weeks andisolating the solid.

Crystalline Form B of compound 9 may be identified by a broad endothermat about 214° C., followed by an exothermic peak at about 217° C. Theendothermic peak has an onset temperature of 210° C. A person skilled inthe art would recognize that the peak and onset temperatures of theendothermic and the endotherms may vary depending on the experimentalconditions. Crystalline Form B of compound 9 may also be identified byan X-ray powder diffraction pattern essentially as shown in Table 1 andFIG. 2 wherein the XRPD patterns were measured using a powderdiffractometer equipped with a Cu X-ray tube source. The sample wasilluminated with Cu Kα₁ radiation and XRPD data were collected fromabout 4 to about 40° 2 theta (2θ). A person skilled in the art wouldrecognize that relative intensities of the XPRD peaks may significantlyvary depending on the orientation of the sample under test and on thetype and setting of the instrument used, so that the intensities in theXPRD traces included herein are to such extent illustrative and are notintended to be used for absolute comparisons.

FIG. 2 is an X-ray powder diffraction pattern of crystalline Form B ofcompound 9 collected from about 4 to about 40 degrees 2θ. The peakscorresponding to the X-ray powder diffraction pattern having a relativeintensity greater than or equal to 5% are listed in Table 1.

FIG. 3 shows a DSC thermogram of crystalline Form B of compound 9exhibiting a broad endothermic peak at about 214° C. followed byexothermic peak at about 217° C. The endothermic peak has an onsettemperature of 210° C. A person skilled in the art would recognize thatthe peak and onset temperatures of the endotherms may vary depending onthe experimental conditions. Data in FIG. 3 was collected as follows: asample of approximately 1-2 mg was weighed into an aluminum pan that wascrimped using lids with either one pin-hole lids. The DSC sample wasscanned from 25° C. to temperatures indicated in the plots at a heatingrate of 10° C./min with 50 mL/min nitrogen flow. The samples run undermodulated DSC (MDSC) were modulated + and −1° C. every 60 seconds withramp rates of 2 or 3° C./min. Data was collected and analyzed by TRIOS(TA Instruments, New Castle, Del.)

FIG. 4 is a TGA (thermal gravimetric analysis) thermogram of crystallineForm B of compound 9 exhibiting an onset weight loss at about 218° C.and scanned from room temperature to about 300° C. at a heating rate of10° C./min.

In one embodiment, the present invention provides a solid Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

In one embodiment, the present invention provides a crystalline Form Bof(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

In another embodiment, the crystalline Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate is characterized by an X-ray powder diffractionpattern (XPRD) comprising at least three approximate peak positions(degrees 2 theta [2θ]±0.2) when measured using Cu K_(α) radiation,selected from the group consisting of 4.4, 12.7, 13.3, 14.7, 15.2, 16.4,18.0, 19.1, 19.3, 19.9, 20.2, 20.5, 21.0, 22.2, 23.5 24.2, 24.8, 26.3,29.6, 30.1 and 31.3, when the XPRD is collected from about 4 to about 40degrees 2 theta (2θ).

In another embodiment, the crystalline Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate is characterized by an X-ray powder diffractionpattern (XPRD) comprising at least three approximate peak positions(degrees 2 theta±0.2) when measured using Cu K_(a) radiation, selectedfrom the group consisting of 4.4, 16.4, 19.3, 22.2, 23.5, 26.3, 29.6 and30.1 when the XPRD is collected from about 4 to about 40 degrees 2θ.

In another embodiment, the crystalline Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate is characterized by an X-ray powder diffractionpattern, as measured using Cu K_(α) radiation, substantially similar toFIG. 2.

In another embodiment, the crystalline Form B of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate is further characterized by an endothermic peakhaving an onset temperature at about 210° C. as measured by differentialscanning calorimetry in which the temperature is scanned at 2-3° C. perminute.

In another embodiment, the present invention provides a method forpreparing crystalline Form B of compound 9 comprising suspending a solidmaterial of the free form in a solvent system comprising one or moreorganic solvents or a mixture of one or more organic solvents and waterand isolating the solid.

In another embodiment, the present invention provides a process forpreparing solid Form B of compound 9, comprising contacting compound 9with water, an organic solvent, a mixture of organic solvents or amixture of an organic solvent and water at a suitable temperature,stirring for up to 4 weeks and isolating the solid.

In another embodiment, the present invention provides a process forpreparing crystalline Form B of compound 9, comprising directcrystallization from a reaction mixture with or without seeding withForm B. In one embodiment, the direct crystallization is from a finaldeprotection step wherein compound 20 is heated to a suitabletemperature in a suitable solvent mixture with a suitable acidic reagentfor a suitable period of time. In one embodiment, the suitable organicsolvent mixture is water and acetonitrile, the suitable acidic reagentis acetic acid, the suitable temperature is between 50° C. and 100° C.and the suitable time is between 10 and 240 minutes.

In one embodiment, the direct crystallization process comprises treatingdi-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (123.2 g, 196 mmole) in a 3 liter flask with acetonitrile(1.23 L), acetic acid (616 ml) water (616 ml) and heating with stirringat 70° C. for 1.1 hours, then treating the mixture with a few seedcrystals of Form B of4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate, letting the mixture stir at 70° C. until cloudy,then turning off the heat and allowing the mixture to cool to roomtemperature. After stirring overnight, crystalline solids were collectedby filtration and dried in a vacuum oven to constant weight to give 84.0grams of crystalline Form B of4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

In another embodiment, crystalline Form B is chemically and physicallystable for at least one month at 5° C./dry, 40° C./dry, 25° C. withrelative humidity of up to 60%; and 40° C. with relative humidity of upto 75%. In another embodiment, crystalline Form B is chemically andphysically stable for at least three months in all conditions including,but not limited to open dish at 40° C., 40° C. with relative humidity ofup to 75%, 25° C. with relative humidity of up to 60% and closed dish at5° C. with a desiccator. Chemically and physically stable means nochanges were observed on the X-ray powder diffraction and HPLC impurityprofiles (e.g., less than 0.2% variance) and there were no observedchanges in physical appearance of the samples.

TABLE 1 XRPD pattern peaks for crystalline Form B of 4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl dihydrogen phosphate Peak Position RelativeIntensity No. [°2θ] [%] 1 4.43 13.6 2 12.74 2.3 3 13.29 4.5 4 14.70 1.95 15.19 8.6 6 16.42 13.9 7 17.99 5.3 8 19.12 10.4 9 19.34 15.8 10 19.858.8 11 20.19 11.1 12 20.45 12.3 13 21.03 11.2 14 22.20 100.0 15 23.5230.6 16 24.21 11.5 17 24.81 11.7 18 26.33 21.2 19 29.59 13.1 20 30.0515.8 21 31.28 10.5

In one embodiment, the present invention provides an amorphous Form C of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate.

In another embodiment, the amorphous Form C of compound 9 ischaracterized by an X-ray powder diffraction pattern (XPRD) using CuK_(a) radiation, characterized by a broad halo with no discernablediffraction peak.

In yet another embodiment, the present invention provides a method forpreparing amorphous Form C of compound 9 comprising spray drying asolution of compound 9 with or without co-polymer.

In one embodiment, the present application provides a process forpreparing solid Form C of the compound 9. In some embodiments, theamorphous material is collected after being precipitated from a solventor from a solution after concentrating the solution by evaporating someof the solvent, for example, using a rotator evaporator. Alternatively,adding a second solvent to the mixture may precipitate Form C.

Compound 9 may be converted to amorphous solid Form C using any methodknown to those skilled in the art. The amorphous compound 9 may becharacterized by the absence of a diffraction pattern characteristic ofa crystalline form. The X-ray powder diffraction of a partiallyamorphous Form C may still lack features characteristic of a crystalform because the diffraction peaks from the crystalline portion of thesample may be too weak to be observable over the noise. FIG. 5 is anX-ray powder diffraction pattern of an amorphous Form X of compound 9.

In one embodiment, the amorphous Form C of compound 9 may be prepared byspray drying a solution of the compound in appropriate solvent. Spraydrying is well known in the art and is often used to drythermally-sensitive materials such as pharmaceutical drugs. Spray dryingalso provides consistent particle distribution that can be reproducedfairly well. Any gas may be used to dry the powder although air iscommonly used. If the material is sensitive to air, an inert gas, suchnitrogen or argon, may be used. Any method that converts a solution,slurry, suspension or an emulsion of the compound to produce a solidpowder may be suitable for amorphous Form C of compound 9.

In one embodiment, a solution of compound 9 in a polar solvent may bespray dried using a nanospray dryer equipped a condenser. The inlettemperature may be kept between 70-120° C.

It is to be understood that crystalline Form B of compound 9 andamorphous solid Form C of compound 9, in addition to having the XRPD,DSC, TGA and other characteristics described herein, may also possessother characteristics not described, such as but not limited to thepresence of water or one or more solvent molecules.

X-Ray Powder Diffraction (XRPD):

The powder x-ray diffraction measurements were performed usingPANalytical's X-pert Pro diffractometer at room temperature with copperradiation (1.54060 A). The incident beam optic was comprised of avariable divergence slit to ensure a constant illuminated length on thesample and on the diffracted beam side; a fast linear solid statedetector was used with an active length of 2.12 degrees 2 theta measuredin a scanning mode. The powder sample was packed on the indented area ofa zero background silicon holder and spinning was performed to achievebetter statistics. A symmetrical scan was measured from 4-40 degrees 2theta (2θ) with a step size of 0.017 degrees and a scan step time of15.5 s.

Differential Scanning Calorimetry (DSC):

DSC was performed on a sample of the material using a Discovery DSCdifferential scanning calorimeter (TA Instruments, New Castle, Del.).The instrument was calibrated with indium. A sample of approximately 1-2mg was weighed into an aluminum pan that was crimped using lids witheither one pin-hole lids. The DSC samples were scanned from 25° C. totemperatures indicated in the plots at a heating rate of 10° C./min with50 mL/min nitrogen flow. The samples run under modulated DSC (MDSC) weremodulated + and −1° C. every 60 s with ramp rates of 2 or 3° C./min.Data was collected and analyzed by TRIOS (TA Instruments, New Castle,Del.).

Thermogravimetric Analysis (TGA):

A Model Discovery TGA, Thermogravimetric Analyzer (TA Instruments, NewCastle, Del.) was used for TGA measurement. A sample with weight ofapproximately 2-5 mg was scanned from room temperature to temperaturesindicated on the plots at a heating rate of 10° C./min. Data wascollected and analyzed by TRIOS software (TA Instruments, New Castle,Del.).

Compounds names in the present invention were generated usingChemBioDrawUltra version 12.0 from Cambridge Soft/Chem Office 2010.

TABLE 2 Compound Numbers, Structures and Chemical Names 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

In one embodiment, the compound is(4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(4,5-dichloro-2-(4-fluorophenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluoro-2-methoxyphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluorophenoxy)-4-(perfluoroethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(5-chloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(2-oxo-4-(2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(2-chloro-4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(5-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(4-chloro-2-(4-fluoro-2-methylphenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(5-chloro-2-(2-chloro-4-fluorophenoxy)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(2-oxo-4-(2-(o-tolyloxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(2,4-difluorophenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(2-oxo-4-(2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamido)pyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is(4-(2-(4-fluorophenoxy)-5-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate or a pharmaceutically acceptable salt thereof.

Compositions, Uses, Formulation, Administration and Additional Agents

Pharmaceutically Acceptable Compositions

As discussed herein, the invention provides compounds that areinhibitors of voltage-gated sodium channels, and thus the presentcompounds are useful for the treatment of diseases, disorders, andconditions including, but not limited to chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence, pathological cough, or cardiac arrhythmia.Accordingly, in another aspect of the invention, pharmaceuticallyacceptable compositions are provided, wherein these compositionscomprise any of the compounds as described herein, and optionallycomprise a pharmaceutically acceptable carrier, adjuvant or vehicle. Incertain embodiments, these compositions optionally further comprise oneor more additional therapeutic agents.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgement, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt of this invention that, uponadministration to a recipient, is capable of providing, either directlyor indirectly, a compound of this invention or an inhibitorily activemetabolite or residue thereof. As used herein, the term “inhibitorilyactive metabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of a voltage-gated sodium channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

As described herein, the pharmaceutically acceptable compositions of theinvention additionally comprise a pharmaceutically acceptable carrier,adjuvant, or vehicle, which, as used herein, includes any and allsolvents, diluents, or other liquid vehicle, dispersion or suspensionaids, surface active agents, isotonic agents, thickening or emulsifyingagents, preservatives, solid binders, lubricants and the like, as suitedto the particular dosage form desired. Remington's PharmaceuticalSciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton,Pa., 1980) discloses various carriers used in formulatingpharmaceutically acceptable compositions and known techniques for thepreparation thereof. Except insofar as any conventional carrier mediumis incompatible with the compounds of the invention, such as byproducing any undesirable biological effect or otherwise interacting ina deleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, its use is contemplated to be within the scopeof this invention. Some examples of materials which can serve aspharmaceutically acceptable carriers include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, serum proteins,such as human serum albumin, buffer substances such as phosphates,glycine, sorbic acid, or potassium sorbate, partial glyceride mixturesof saturated vegetable fatty acids, water, salts or electrolytes, suchas protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesiumtrisilicate, polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

In another aspect, the invention features a pharmaceutical compositioncomprising the compound of the invention and a pharmaceuticallyacceptable carrier.

In another aspect, the invention features a pharmaceutical compositioncomprising a therapeutically effective amount of the compounds offormula I and one or more pharmaceutically acceptable carriers orvehicles.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject a compound of formula I or a pharmaceutical compositionthereof. In another aspect, the voltage-gated sodium channel is NaV1.8.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of chronic pain, gut pain,neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain,cancer pain, idiopathic pain, multiple sclerosis, Charcot-Marie-Toothsyndrome, incontinence, pathological cough, or cardiac arrhythmiacomprising administering an effective amount of a compound to thesubject, or a pharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain wherein said method comprises administeringan effective amount of a compound, or a pharmaceutical composition ofthe compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain, whereinneuropathic pain comprises post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma,traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain; nerveavulsion injury, brachial plexus avulsion injury, complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia, post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia wherein said methodcomprises administering an effective amount of a compound, or apharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of musculoskeletal pain, whereinmusculoskeletal pain comprises osteoarthritis pain, back pain, coldpain, burn pain or dental pain wherein said method comprisesadministering an effective amount of a compound, or a pharmaceuticalcomposition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain or vulvodyniawherein said method comprises administering an effective amount of acompound, or a pharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of inflammatory pain, whereininflammatory pain comprises rheumatoid arthritis pain wherein saidmethod comprises administering an effective amount of a compound, or apharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of idiopathic pain, whereinidiopathic pain comprises fibromyalgia pain wherein said methodcomprises administering an effective amount of a compound, or apharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method of treating orlessening the severity in a subject of pathological cough wherein saidmethod comprises administering an effective amount of a compound, or apharmaceutical composition of the compound of formula I.

In yet another aspect, the invention features a method wherein thesubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith an effective amount of a compound, or a pharmaceutical compositionof the compound of formula I.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a subject comprising administering tothe subject an effective amount of a compound, or a pharmaceuticalcomposition of the compound of formula I. In another aspect, thevoltage-gated sodium channel is Na_(V)1.8.

In another aspect, the invention features a method of inhibiting avoltage-gated sodium channel in a biological sample comprisingcontacting the biological sample with an effective amount of a compound,or a pharmaceutical composition of the compound of formula I. In anotheraspect, the voltage-gated sodium channel is Na_(V)1.8.

In another aspect, the invention features a method of treating orlessening the severity in a subject of acute pain, chronic pain,neuropathic pain, inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy, epilepsy conditions, neurodegenerative disorders, psychiatricdisorders, anxiety, depression, dipolar disorder, myotonia, arrhythmia,movement disorders, neuroendocrine disorders, ataxia, multiplesclerosis, irritable bowel syndrome, incontinence, pathological cough,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head pain, neck pain,severe pain, intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, cancer pain, stroke, cerebral ischemia, traumaticbrain injury, amyotrophic lateral sclerosis, stress induced angina,exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility, comprising administering an effective amountof a compound, or a pharmaceutical composition of the compound offormula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of femur cancer pain, non-malignantchronic bone pain, rheumatoid arthritis, osteoarthritis, spinalstenosis, neuropathic low back pain, myofascial pain syndrome;fibromyalgia, temporomandibular joint pain, chronic visceral pain,abdominal pain, pancreatic pain, IBS pain, chronic and acute headachepain; migraine, tension headache, cluster headaches, chronic and acuteneuropathic pain, post-herpetic neuralgia, diabetic neuropathy,HIV-associated neuropathy, trigeminal neuralgia, Charcot-Marie Toothneuropathy, hereditary sensory neuropathy, peripheral nerve injury,painful neuromas, ectopic proximal and distal discharges; radiculopathy,chemotherapy induced neuropathic pain, radiotherapy-induced neuropathicpain, post-mastectomy pain, central pain, spinal cord injury pain,post-stroke pain, thalamic pain, complex regional pain syndrome, phantompain, intractable pain, acute pain, acute post-operative pain, acutemusculoskeletal pain, joint pain, mechanical low back pain, neck pain,tendonitis, injury pain, exercise pain, acute visceral pain,pyelonephritis, appendicitis, cholecystitis, intestinal obstruction,hernias, chest pain, cardiac pain; pelvic pain, renal colic pain, acuteobstetric pain, labor pain; cesarean section pain, acute inflammatorypain, burn pain, trauma pain, acute intermittent pain, endometriosis,acute herpes zoster pain, sickle cell anemia, acute pancreatitis,breakthrough pain, orofacial pain, sinusitis pain, dental pain, multiplesclerosis (MS) pain, pain in depression, leprosy pain, Behcet's diseasepain, adiposis dolorosa, phlebitic pain, Guillain-Barre pain, painfullegs and moving toes; Haglund syndrome, erythromelalgia pain, Fabry'sdisease pain, bladder and urogenital disease, urinary incontinence,pathological cough, hyperactivebladder, painful bladder syndrome,interstitial cyctitis (IC), prostatitis, complex regional pain syndrome(CRPS) type I, complex regional pain syndrome (CRPS), type II,widespread pain, paroxysmal extreme pain, pruritis, tinnitis, orangina-induced pain, comprising administering an effective amount of acompound, or a pharmaceutical composition of the compound of formula I.

In another aspect, the invention features a method of treating orlessening the severity in a subject of neuropathic pain comprisingadministering an effective amount of a compound, or a pharmaceuticalcomposition of the compound of formula I. In one aspect, the neuropathicpain is selected from post-herpetic neuralgia, diabetic neuralgia,painful HIV-associated sensory neuropathy, trigeminal neuralgia, burningmouth syndrome, post-amputation pain, phantom pain, painful neuroma,traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinalstenosis, carpal tunnel syndrome, radicular pain, sciatica pain, nerveavulsion injury, brachial plexus avulsion, complex regional painsyndrome, drug therapy induced neuralgia, cancer chemotherapy inducedneuralgia, anti-retroviral therapy induced neuralgia, post spinal cordinjury pain, idiopathic small-fiber neuropathy, idiopathic sensoryneuropathy or trigeminal autonomic cephalalgia.

Manufacture of Medicaments

In one aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in inhibiting a voltage-gated sodium channel. Inanother aspect, the voltage-gated sodium channel is Na_(V)1.8.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity in a subject ofchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathologicalcough, or cardiac arrhythmia.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity in a subject ofgut pain, wherein gut pain comprises inflammatory bowel disease pain,Crohn's disease pain or interstitial cystitis pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in a treating or lessening the severity in a subjectof neuropathic pain, wherein neuropathic pain comprises post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma; traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion injury, complex regional pain syndrome, drugtherapy induced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic neuropathy.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity in a subject ofmusculoskeletal pain, wherein musculoskeletal pain comprisesosteoarthritis pain, back pain, cold pain, burn pain or dental pain.

In yet another aspect, the invention the invention provides the use of acompound or pharmaceutical composition of formula I for the manufactureof a medicament for use in treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain or vulvodynia.

In yet another aspect, the invention the invention provides the use of acompound or pharmaceutical composition of formula I for the manufactureof a medicament for use in treating or lessening the severity in asubject of inflammatory pain, wherein inflammatory pain comprisesrheumatoid arthritis pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity in a subject ofidiopathic pain, wherein idiopathic pain comprises fibromyalgia pain.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity in a subject ofpathological cough.

In yet another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament in combination with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound or pharmaceutical composition.

In another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity of acute pain,chronic pain, neuropathic pain, inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy, epilepsy conditions, neurodegenerative disorders,psychiatric disorders, anxiety, depression, dipolar disorder, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, pathologicalcough, visceral pain, osteoarthritis pain, postherpetic neuralgia,diabetic neuropathy, radicular pain, sciatica, back pain, head pain,neck pain, severe pain, intractable pain, nociceptive pain, breakthroughpain, postsurgical pain, cancer pain, stroke, cerebral ischemia,traumatic brain injury, amyotrophic lateral sclerosis, stress inducedangina, exercise induced angina, palpitations, hypertension, or abnormalgastro-intestinal motility.

In another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity of femur cancerpain, non-malignant chronic bone pain, rheumatoid arthritis,osteoarthritis, spinal stenosis, neuropathic low back pain, myofascialpain syndrome, fibromyalgia, temporomandibular joint pain, chronicvisceral pain, abdominal pain, pancreatic pain, IBS pain, chronic andacute headache pain, migraine, tension headache, cluster headaches,chronic and acute neuropathic pain, post-herpetic neuralgia, diabeticneuropathy, HIV-associated neuropathy, trigeminal neuralgia,Charcot-Marie Tooth neuropathy, hereditary sensory neuropathy,peripheral nerve injury, painful neuromas, ectopic proximal and distaldischarges, radiculopathy, chemotherapy induced neuropathic pain,radiotherapy-induced neuropathic pain, post-mastectomy pain, centralpain, spinal cord injury pain, post-stroke pain, thalamic pain, complexregional pain syndrome, phantom pain, intractable pain, acute pain,acute post-operative pain, acute musculoskeletal pain, joint pain,mechanical low back pain, neck pain, tendonitis, injury pain, exercisepain, acute visceral pain, pyelonephritis, appendicitis, cholecystitis,intestinal obstruction, hernias, chest pain, cardiac pain, pelvic pain,renal colic pain, acute obstetric pain, labor pain, cesarean sectionpain, acute inflammatory pain, burn pain, trauma pain, acuteintermittent pain, endometriosis, acute herpes zoster pain, sickle cellanemia, acute pancreatitis, breakthrough pain, orofacial pain, sinusitispain, dental pain, multiple sclerosis (MS) pain, pain in depression,leprosy pain, Behcet's disease pain, adiposis dolorosa, phlebitic pain,Guillain-Barre pain, painful legs and moving toes, Haglund syndrome,erythromelalgia pain, Fabry's disease pain, bladder and urogenitaldisease, urinary incontinence, pathological cough, hyperactive bladder,painful bladder syndrome, interstitial cyctitis (IC), prostatitis,complex regional pain syndrome (CRPS) type I complex regional painsyndrome (CRPS) type II, widespread pain, paroxysmal extreme pain,pruritis, tinnitis, or angina-induced pain.

In another aspect, the invention provides the use of a compound orpharmaceutical composition of formula I for the manufacture of amedicament for use in treating or lessening the severity of neuropathicpain. In one aspect, the neuropathic pain is selected from post-herpeticneuralgia, diabetic neuralgia, painful HIV-associated sensoryneuropathy, trigeminal neuralgia, burning mouth syndrome,post-amputation pain, phantom pain, painful neuroma, traumatic neuroma,Morton's neuroma, nerve entrapment injury, spinal stenosis, carpaltunnel syndrome, radicular pain, sciatica pain, nerve avulsion injury,brachial plexus avulsion, complex regional pain syndrome, drug therapyinduced neuralgia, cancer chemotherapy induced neuralgia,anti-retroviral therapy induced neuralgia, post spinal cord injury pain,idiopathic small-fiber neuropathy, idiopathic sensory neuropathy ortrigeminal autonomic cephalalgia.

Administration of Pharmaceutically Acceptable Compositions.

In certain embodiments of the invention an “effective amount” of thecompound, or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofchronic pain, gut pain, neuropathic pain, musculoskeletal pain, acutepain, inflammatory pain, cancer pain, idiopathic pain, multiplesclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathologicalcough, or cardiac arrhythmia.

The compounds and compositions, according to the methods of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of the pain or non-pain diseases recited herein. The exactamount required will vary from subject to subject, depending on thespecies, age, and general condition of the subject, the severity of theinfection, the particular agent, its mode of administration, and thelike. The compounds of the invention are preferably formulated in dosageunit form for ease of administration and uniformity of dosage. Theexpression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the subject to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular subject or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the subject; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts. The term “subject” or “patient,” as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the invention, it isoften desirable to slow the absorption of the compound from subcutaneousor intramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the compound then depends upon itsrate of dissolution that, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered compound form is accomplished by dissolving or suspendingthe compound in an oil vehicle. Injectable depot forms are made byforming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the inventioncontemplates the use of transdermal patches, which have the addedadvantage of providing controlled delivery of a compound to the body.Such dosage forms are prepared by dissolving or dispensing the compoundin the proper medium. Absorption enhancers can also be used to increasethe flux of the compound across the skin. The rate can be controlled byeither providing a rate controlling membrane or by dispersing thecompound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas inhibitors of voltage-gated sodium channels. In one embodiment, thecompounds and compositions of the invention are inhibitors of Na_(V)1.8and thus, without wishing to be bound by any particular theory, thecompounds and compositions are particularly useful for treating orlessening the severity of a disease, condition, or disorder whereactivation or hyperactivity of Na_(V)1.8 is implicated in the disease,condition, or disorder. When activation or hyperactivity of Na_(V)1.8 isimplicated in a particular disease, condition, or disorder, the disease,condition, or disorder may also be referred to as a “Na_(V)1.8-mediateddisease, condition or disorder.” Accordingly, in another aspect, theinvention provides a method for treating or lessening the severity of adisease, condition, or disorder where activation or hyperactivity ofNa_(V)1.8 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor ofNa_(V)1.8 may be assayed according to methods described generally in theExamples herein, or according to methods available to one of ordinaryskill in the art.

Additional Therapeutic Agents

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the invention can be employed in combinationtherapies, that is, the compounds and pharmaceutically acceptablecompositions can be administered concurrently with, prior to, orsubsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.” For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such saNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNSpathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, NineteenthEdition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp & DohmeCorp., a subsidiary of Merck & Co., Inc., 2011, and the Food and DrugAdministration website, www.fda.gov, the entire contents of which arehereby incorporated by reference.

In another embodiment, additional appropriate therapeutic agents areselected from the following:

(1) an opioid analgesic, e.g. morphine, heroin, hydromorphone,oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl,cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene,nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol,nalbuphine or pentazocine;

(2) a nonsteroidal antiinflammatory drug (NSAID), e.g. aspirin,diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac;

(3) a barbiturate sedative, e.g. amobarbital, aprobarbital,butabarbital, butabital, mephobarbital, metharbital, methohexital,pentobarbital, phenobartital, secobarbital, talbutal, theamylal orthiopental;

(4) a benzodiazepine having a sedative action, e.g. chlordiazepoxide,clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam ortriazolam;

(5) a histamine (H₁) antagonist having a sedative action, e.g.diphenhydramine, pyrilamine, promethazine, chlorpheniramine orchlorcyclizine;

(6) a sedative such as glutethimide, meprobamate, methaqualone ordichloralphenazone;

(7) a skeletal muscle relaxant, e.g. baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol or orphrenadine;

(8) an NMDA receptor antagonist, e.g. dextromethorphan((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine,EN-3231 (MorphiDex®), a combination formulation of morphine anddextromethorphan), topiramate, neramexane or perzinfotel including anNR2B antagonist, e.g. ifenprodil, traxoprodil or(−)—(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

(9) an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine,guanfacine, dexmetatomidine, modafinil, or4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline;

(10) a tricyclic antidepressant, e.g. desipramine, imipramine,amitriptyline or nortriptyline;

(11) an anticonvulsant, e.g. carbamazepine (Tegretol®), lamotrigine,topiramate, lacosamide (Vimpat®) or valproate;

(12) a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g.(alphaR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

(13) a muscarinic antagonist, e.g oxybutynin, tolterodine, propiverine,tropsium chloride, darifenacin, solifenacin, temiverine and ipratropium;

(14) a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, or lumiracoxib;

(15) a coal-tar analgesic, in particular paracetamol;

(16) a neuroleptic such as droperidol, chlorpromazine, haloperidol,perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine,clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole,aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone,raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride,balaperidone, palindore, eplivanserin, osanetant, rimonabant,meclinertant, Miraxion® or sarizotan;

(17) a vanilloid receptor agonist (e.g. resinferatoxin or civamide) orantagonist (e.g. capsazepine, GRC-15300);

(18) a beta-adrenergic such as propranolol;

(19) a local anaesthetic such as mexiletine;

(20) a corticosteroid such as dexamethasone;

(21) a 5-HT receptor agonist or antagonist, particularly a 5-HT_(1B/1D)agonist such as eletriptan, sumatriptan, naratriptan, zolmitriptan orrizatriptan;

(22) a 5-HT_(2A) receptor antagonist such asR(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol(MDL-100907);

(23) a cholinergic (nicotinic) analgesic, such as ispronicline(TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403),(R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;

(24) Tramadol®, Tramadol ER (Ultram ER®), Tapentadol ER (Nucynta®);

(25) a PDE5 inhibitor, such as5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one(sildenafil),(6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2′,1′:6,1]-pyrido[3,4-b]indole-1,4-dione(IC-351 or tadalafil),2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one(vardenafil),5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one,4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide,3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

(26) an alpha-2-delta ligand such as gabapentin (Neurontin®), gabapentinGR (Gralise®), gabapentin, enacarbil (Horizant®), pregabalin (Lyrica®),3-methyl gabapentin,(1[alpha],3[alpha],5[alpha])(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-aceticacid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-heptanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline,[(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid,3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one,C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine,(3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid,(3S,5R)-3-aminomethyl-5-methyl-octanoic acid,(3S,5R)-3-amino-5-methyl-nonanoic acid,(3S,5R)-3-amino-5-methyl-octanoic acid,(3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and(3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid;

(27) a cannabinoid such as KHK-6188;

(28) metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

(29) a serotonin reuptake inhibitor such as sertraline, sertralinemetabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetinedesmethyl metabolite), fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine and trazodone;

(30) a noradrenaline (norepinephrine) reuptake inhibitor, such asmaprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine,tomoxetine, mianserin, buproprion, buproprion metabolitehydroxybuproprion, nomifensine and viloxazine (Vivalan®), especially aselective noradrenaline reuptake inhibitor such as reboxetine, inparticular (S,S)-reboxetine;

(31) a dual serotonin-noradrenaline reuptake inhibitor, such asvenlafaxine, venlafaxine metabolite O-desmethylvenlafaxine,clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine(Cymbalta®), milnacipran and imipramine;

(32) an inducible nitric oxide synthase (iNOS) inhibitor such asS-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine,S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine,S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine,(2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenoic acid,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile,(2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolebutanol,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile,2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile,N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine,NXN-462, or guanidinoethyldisulfide;

(33) an acetylcholinesterase inhibitor such as donepezil;

(34) a prostaglandin E2 subtype 4 (EP4) antagonist such asN-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)-carbonyl]-4-methylbenzenesulfonamideor4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoicacid;

(35) a leukotriene B4 antagonist; such as1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylicacid (CP-105696),5-[2-(2-Carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valericacid (ONO-4057) or DPC-11870;

(36) a 5-lipoxygenase inhibitor, such as zileuton,6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone(ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone(CV-6504);

(37) a sodium channel blocker, such as lidocaine, lidocaine plustetracaine cream (ZRS-201) or eslicarbazepine acetate;

(38) an Na_(V)1.7 blocker, such as XEN-402, XEN403, TV-45070,PF-05089771, CNV1014802, GDC-0276, RG7893 and such as those disclosed inWO2011/140425; WO2012/106499; WO2012/112743; WO2012/125613,WO2012/116440, WO2011026240, U.S. Pat. Nos. 8,883,840, 8,466,188, orPCT/US2013/21535 the entire contents of each application herebyincorporated by reference.

(38a) an Na_(V)1.7 blocker such as(2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl)-(4-isopropoxy-3-methyl-phenyl)methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone,1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol,(4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carbonyl]phenyl]pyridine-2-carbonitrile,(4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,(4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,2,2,2-trifluoro-1-[1′-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[(3S)-2,3-dimethyl-1′-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2,2-trifluoro-ethanone,[8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone,2,2,2-trifluoro-1-[1′-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]ethanone,1-[1′-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl]-2,2-dimethyl-propan-1-one,(4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone,[2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone,4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamideor(3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-yl]methanone.

(39) an Na_(V)1.8 blocker, such as PF-04531083, PF-06372865 and such asthose disclosed in WO2008/135826, WO2006/011050, WO2013/061205,US20130303535, WO2013131018, U.S. Pat. No. 8,466,188, WO2013114250,WO2014/1280808, WO2014/120815 and WO2014/120820, the entire contents ofeach application hereby incorporated by reference.

(39a) an Na_(V)1.8 blocker such as4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide,5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide,2-((5-fluoro-2-hydroxybenzyl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide,2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide,N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide,In one embodiment, the compound is3-(4-fluoro-2-methoxyphenoxy)-N-(3-(methylsulfonyl)phenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(2-chloro-4-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,3-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,2-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide,3-(2,4-difluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)quinoline-3-carboxamide,N-(3-sulfamoylphenyl)-3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamide,3-(4-chloro-2-methylphenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,5-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)picolinicacid,3-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)quinoxaline-2-carboxamide,3-(4-fluoro-2-methoxyphenoxy)-N-(pyridin-4-yl)quinoxaline-2-carboxamide,3-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide,N-(3-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,N-(4-carbamoylphenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,4-(3-(4-(trifluoromethoxy)phenoxy)quinoxaline-2-carboxamido)benzoicacid,N-(4-cyanophenyl)-3-(4-fluoro-2-methoxyphenoxy)quinoxaline-2-carboxamide,5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinic acid,5-(2-(2,4-dimethoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4,6-bis(trifluoromethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,5-(2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)benzamido)picolinicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzoicacid, 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid,4-(2-(2-chloro-4-fluorophenoxy)-4-(perfluoroethyl)benzamido)benzoicacid,4-(2-(4-fluoro-2-methylphenoxy)-4-(perfluoroethyl)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)benzoicacid, 4-(4,5-dichloro-2-(4-chloro-2-methylphenoxy)benzamido)benzoicacid, 5-(4-(tert-butyl)-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinicacid, 5-(4,5-dichloro-2-(4-(trifluoromethoxy)phenoxy)benzamido)picolinicacid, 4-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)benzoicacid, 5-(4,5-dichloro-2-(2,4-dimethoxyphenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(2-chloro-4-fluorophenoxy)benzamido)picolinic acid,5-(4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamido)picolinic acid,4-(4,5-dichloro-2-(4-chloro-2-methoxyphenoxy)benzamido)benzoic acid,5-(4,5-dichloro-2-(2,4-difluorophenoxy)benzamido)picolinic acid,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-6-(trifluoromethyl)benzamide,2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluorophenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-chloro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide,5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-chloro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)benzamide,2,4-dichloro-6-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)-4,6-bis(trifluoromethyl)benzamide,5-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethoxy)benzamide,2-(4-fluoro-2-methoxyphenoxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide,4,5-dichloro-2-(4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(4-fluoro-2-methoxyphenoxy)-4-(perfluoroethyl)-N-(3-sulfamoylphenyl)benzamide,5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(3-sulfamoylphenyl)benzamide,2-(2-chloro-4-fluorophenoxy)-4-cyano-N-(3-sulfamoylphenyl)benzamide orN-(3-sulfamoylphenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide.

(40) a combined Na_(V)1.7 and Na_(V)1.8 blocker, such as DSP-2230 orBL-1021;

(41) a 5-HT3 antagonist, such as ondansetron;

(42) a TPRV 1 receptor agonist, such as capsaicin (NeurogesX®,Qutenza®); and the pharmaceutically acceptable salts and solvatesthereof;

(43) a nicotinic receptor antagonist, such as varenicline;

(44) an N-type calcium channel antagonist, such as Z-160;

(45) a nerve growth factor antagonist, such as tanezumab;

(46) an endopeptidase stimulant, such as senrebotase;

(47) an angiotensin II antagonist, such as EMA-401;

In one embodiment, the additional appropriate therapeutic agents areselected from V-116517, Pregbalin, controlled release Pregbalin,Ezogabine (Potiga®), Ketamine/amitriptyline topical cream (Amiket®),AVP-923, Perampanel (E-2007), Ralfinamide, transdermal bupivacaine(Eladur®), CNV1014802, JNJ-10234094 (Carisbamate), BMS-954561 orARC-4558.

In another embodiment, the additional appropriate therapeutic agents areselected fromN-(6-amino-5-(2,3,5-trichlorophenyl)pyridin-2-yl)acetamide;N-(6-amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide;or3-((4-(4-(trifluoromethoxy)phenyl)-1H-imidazol-2-yl)methyl)oxetan-3-amine.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. The amount of additional therapeutic agent in thepresently disclosed compositions will range from about 10% to 100% ofthe amount normally present in a composition comprising that agent asthe only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, theinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the invention as describedgenerally above, and in classes and subclasses herein, and a carriersuitable for coating said implantable device. In still another aspect,the invention includes an implantable device coated with a compositioncomprising a compound of the invention as described generally above, andin classes and subclasses herein, and a carrier suitable for coatingsaid implantable device. Suitable coatings and the general preparationof coated implantable devices are described in U.S. Pat. Nos. 6,099,562;5,886,026; and 5,304,121. The coatings are typically biocompatiblepolymeric materials such as a hydrogel polymer, polymethyldisiloxane,polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinylacetate, and mixtures thereof. The coatings may optionally be furthercovered by a suitable topcoat of fluorosilicone, polysaccarides,polyethylene glycol, phospholipids or combinations thereof to impartcontrolled release characteristics in the composition.

Another aspect of the invention relates to inhibiting Na_(V)1.8 activityin a subject, which method comprises administering to the subject acompound of formula I or a composition comprising said compound. Yetanother aspect of the invention relates to inhibiting Na_(V)1.8 activityin a biological sample, which method comprises contacting saidbiological sample with a compound of formula I or a compositioncomprising said compound. The term “biological sample,” as used herein,includes, without limitation, cell cultures or extracts thereof;biopsied material obtained from a mammal or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof.

Inhibition of Na_(V)1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumchannels in biological and pathological phenomena; and the comparativeevaluation of new sodium channel inhibitors.

SCHEMES AND EXAMPLES

The compounds of the invention may be prepared readily using thefollowing methods. Illustrated below in Scheme 1 is a general method forpreparing the compounds of the present invention.

a) Alkoxy pyridine-4-amine (i.e. 2-methoxypyridin-4-amine), couplingagent (i.e. HATU, EDCI, HOBT), base (i.e. N-methylmorpholine, Et₃N),solvent (i.e., DMF, dichloromethane); (b) SO₂Cl₂, DMF in a solvent(i.e., dichloromethane); (c) 2-Methoxypyridin-4-amine, base (i.e.,pyridine), solvent (i.e., dichloromethane, DMF); (d) TMSI or HBr,solvent (i.e., acetonitrile or acetic acid); (e) base (i.e., Cs₂CO₃,Na₂CO₃, K₂CO₃, NaHCO₃), solvent (i.e., DMF, NMP, dioxane), heat; (f)ClCO₂CH₂Cl, solvent (i.e., CH₂Cl₂, DMF); (g) Phosphorylating reagent(i.e. K(PG₁)₂PO₄ including K(t-Bu)₂PO₄ and the like), (n-Bu)₄NI, solvent(i.e., DMF), base (e.g., DIPEA), heat (i.e., 70° C.); (h) HOAc, H₂O,solvent (i.e., CH₃CN), heat (i.e, 70° C.).

One of skill in the art would recognize that steps (f) and (g) in Scheme1 above may be combined into a single step without isolation of theintermediate chloride.

(i) M⁺OH⁻ or D²⁺(OH⁻)₂, 2-MeTHF; (j) aq H⁺; (k) aq M⁺ OH⁻

Salts of compounds of formula I may be prepared as shown in Scheme 1A.In step (i), a solution of compound I treated with M⁺OH⁻ or D²⁺(OH⁻)₂provides the dianionic form of the compound (X=—PO(O⁻)₂.2M⁺ or—PO(O⁻)₂.D²⁺). The free acid form of the compound (X═PO(OH)₂) may beobtained by treating the dianionic form with aqueous acid. Themonoanionic form of the compound X═PO(OH)O⁻M⁺) may be prepared bytreating the free acid form with one equivalent of M⁺OH⁻.

EXAMPLES

General Methods.

¹H NMR (400 MHz) and ³¹P NMR (162 MHz) spectra were obtained assolutions in an appropriate deuterated solvent such as dimethylsulfoxide-d₆ (DMSO-d₆). Mass spectra (MS) were obtained using an AppliedBiosystems API EX LC/MS system. Compound purity and retention times weredetermined by reverse phase HPLC using a Kinetix C18 column (50×2.1 mm,1.7 μm particle) from Phenomenex (pn: 00B-4475-AN)), and a dual gradientrun from 1-99% mobile phase B over 3 minutes. Mobile phase A=H₂O (0.05%CF₃CO₂H). Mobile phase B=CH₃CN (0.05% CF₃CO₂H). Flow rate=2 mL/min,injection volume=3 μL, and column temperature=50° C. Silica gelchromatography was performed using silica gel-60 with a particle size of230-400 mesh. Pyridine, dichloromethane (CH₂Cl₂), tetrahydrofuran (THF),dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and1,4-dioxane were from Baker or Aldrich and in some cases the reagentswere Aldrich Sure-Seal bottles kept under dry nitrogen. All reactionswere stirred magnetically unless otherwise noted. HATU stands for(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate).

Example 1 Preparation of4-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 4-chloro-2-fluoro-benzoic acid (7.0 g, 40.10 mmol), HATU(15.25 g, 40.10 mmol), 2-methoxypyridin-4-amine (4.98 g, 40.10 mmol) andEt₃N (22.4 mL, 160.4 mmol) in dichloromethane (63.0 mL) was stirred atroom temperature overnight. The crude mixture was purified by columnchromatography eluting with a gradient of ethyl acetate in hexanes(0-50%) to yield 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide(4.35 g, 39%), as a white solid. ESI-MS m/z calc. 280.04, found 281.3(M+1)⁺; Retention time: 1.31 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d6) δ 10.80 (s, 1H), 8.09 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.66(dd, J=10.1, 1.9 Hz, 1H), 7.46 (dd, J=8.3, 1.9 Hz, 1H), 7.21 (m, 2H),3.84 (s, 3H) ppm.

To 4-chloro-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (4.35 g, 15.50mmol) in acetonitrile (145.0 mL) was added TMSI (8.8 mL, 62.0 mmol). Thereaction was stirred at 50° C. overnight. The acetonitrile wasevaporated and the crude solid was triturated with ethyl acetate. Thesolid was isolated by filtration and washed with ethyl acetate to give4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (3.8 g, 92%).ESI-MS m/z calc. 266.02, found 267.1 (M+1)+; Retention time: 1.23minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 7.73(t, J=8.0 Hz, 1H), 7.68 (dd, J=10.1, 1.9 Hz, 1H), 7.60 (d, J=7.1 Hz,1H), 7.47 (dd, J=8.3, 2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.71 (dd,J=7.1, 2.1 Hz, 1H) ppm.

Example 2 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide

A solution of 4-bromo-2-fluoro-benzoyl chloride (2 g, 8.42 mmol) indichloromethane (10.0 mL) was added drop-wise to a mixture of2-methoxypyridin-4-amine (1.0 g, 8.42 mmol), pyridine (2.0 mL, 25.27mmol) and dichloromethane (40.0 mL) at 0° C. The mixture was allowed towarm to room temperature and was stirred at that temperature overnight.The mixture was poured into 1N HCl (200 mL) and dichloromethane (200mL). The layers were separated and the organic layer was dried oversodium sulfate, filtered and concentrated under reduced pressure to give4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (1.2 g, 44%) as anoff-white solid. ESI-MS m/z calc. 323.99, found 325.1 (M+1)⁺; Retentiontime: 1.37 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆) δ 10.80(s, 1H), 8.11-8.06 (m, 1H), 7.79 (dd, J=9.8, 1.7 Hz, 1H), 7.68-7.62 (m,1H), 7.59 (dd, J=8.3, 1.7 Hz, 1H), 7.23-7.18 (m, 2H), 3.84 (s, 3H) ppm.

To a stirred solution of4-bromo-2-fluoro-N-(2-methoxy-4-pyridyl)benzamide (800 mg, 2.46 mmol)and copper (1.6 g, 24.61 mmol) in DMSO (15 mL), in a pressure vessel wasbubbled in 1,1,1,2,2-pentafluoro-2-iodo-ethane (4.1 g, 16.47 mmol) Thevessel was sealed and heated at 120° C. for 16 hours. The reactionmixture was diluted with water and filtered through a plug of silica andthen extracted with ethyl acetate (4×). The organics combined, washedwith brine, dried over Na₂SO₄, filtered and evaporated to dryness toyield a crude mixture that was purified by column chromatography using agradient of ethyl acetate in hexanes (0-40%) to give2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(200 mg, 22%) as an off white solid. ESI-MS m/z calc. 364.06, found365.3 (M+1)+; Retention time: 1.39 minutes (3 minutes run). ¹H NMR (400MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.11 (d, J=6.3 Hz, 1H), 7.95 (dd, J=7.4Hz, 1H), 7.89 (d, J=9.9 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.23-7.19 (m,2H), 3.85 (s, 3H) ppm.

2-fluoro-N-(2-methoxy-4-pyridyl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(200 mg, 0.55 mmol) in HBr in acetic acid (1.3 mL of 33% w/v, 5.49 mmol)was stirred at 100° C. for 2 hours, at this time 1 ml of HBr in aceticacid (33% w/v) was added and the mixture was stirred at 100° C. for 4hours, then cooled to room temperature. The reaction mixture was dilutedwith water and a precipitate formed. The precipitate was filtered off,washed with water (2×), cold methyl-tert-butyl ether and dried undervacuum to give2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(138 mg, 72%) as a light grey solid. ESI-MS m/z calc. 350.05, found351.3 (M+1)+; Retention time: 1.3 minutes (3 minutes run).

Example 3 Preparation of4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide

A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol),4,5-dichloro-2-fluoro-benzoic acid (285.1 mg, 1.36 mmol), HATU (622.4mg, 1.64 mmol) and N-methylmorpholine (299.9 μL, 2.73 mmol) in DMF (3mL) was stirred at room temperature for 16 hours. The reaction mixturewas poured into water and extracted with ethyl acetate (3×). Theorganics were combined, washed with water (3×), brine and dried overNa₂SO₄, filtered through a short plug of silica and evaporated todryness. The material was taken up in HBr (in acetic acid) (6.689 mL of33% w/v, 27.28 mmol) and stirred at 95° C. for 16 h. The solution wascooled to room temperature, filtered and solid product washed with water(2×) and then ether (2×) and dried under vacuum to give4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%)as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)⁺;Retention time: 1.16 minutes (3 minutes run).

Example 4 Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(19)

A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (25.0 g,110.3 mmol) in dichloromethane (125.0 mL) was added drop-wise to amixture of 2-methoxypyridin-4-amine (13.7 g, 110.3 mmol), pyridine (26.8mL, 330.9 mmol) and dichloromethane (500.0 mL) at 0° C. The mixture wasallowed to warm to room temperature and was stirred at that temperatureovernight. The mixture was poured into 1N HCl (200 mL) anddichloromethane (200 mL). The layers were separated and the organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure. The product was slurried in hexane, the hexane wasdecanted and the product was dried under reduced pressure to yield2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (25.7 g,74%) as a cream solid. ESI-MS m/z calc. 314.07, found 315.3 (M+1)⁺;Retention time: 1.49 minutes (3 minutes run). ¹H NMR (400 MHz, DMSO-d₆)δ 10.96 (s, 1H), 8.15-8.04 (m, 1H), 8.00-7.85 (m, 2H), 7.76 (d, J=8.1Hz, 1H), 7.26-7.15 (m, 2H), 3.85 (s, 3H) ppm.

To 2-fluoro-N-(2-methoxy-4-pyridyl)-4-(trifluoromethyl)benzamide (1.00g, 3.18 mmol) in acetic acid (6.0 mL) was added HBr (33% in acetic acid)(3.9 mL of 33% w/v, 15.91 mmol) and the mixture stirred at 100° C. for 6hours. Additional HBr (2 mL, 33% in acetic acid) was added and themixture was stirred at room temperature overnight. The mixture was thenheated at 100° C. for 2 hours before it was cooled to room temperature.The mixture was partitioned between ethyl acetate and water. The layerswere separated and the aqueous layer was extracted with ethyl acetate(3×). The combined organics were washed with water and brine (2×), driedover sodium sulfate, filtered and concentrated under reduced pressure.The solid was slurried in methyl-tert-butyl ether and filtered to give2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide (19)(731 mg, 76%). ESI-MS m/z calc. 301.05, found 301.3 (M+1)⁺; Retentiontime: 1.35 minutes (3 minute run). ¹H NMR (400 MHz, DMSO-d₆) δ 11.33 (s,1H), 10.70 (s, 1H), 7.96-7.85 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.35 (d,J=7.2 Hz, 1H), 6.81 (d, J=1.9 Hz, 1H), 6.41 (dd, J=7.2, 2.1 Hz, 1H) ppm.

Example 5 Preparation ofN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide(5a)

Cs₂CO₃ (651.6 mg, 2 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(60.0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μL, 2 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyieldN-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide(5a) (25.7 mg, 28%). ESI-MS m/z calc. 458.07, found 459.5 (M+1)⁺;Retention time: 1.80 minutes (3 minutes run).

Example 6 Preparation of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a)

A mixture of2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)-benzamide (13.6g, 45.30 mmol), 4-fluoro-2-methyl-phenol (17.1 g, 135.9 mmol), Cs₂CO₃(44.28 g, 135.9 mmol) and DMF (340.0 mL) was heated at 100° C. for 1.5hours. The mixture was cooled to room temperature and was poured intowater (500 mL). The mixture was stirred vigorously for 30 min before itwas filtered. The solid was washed with water (250 mL) and was slurriedwith methyl tert-buthyl ether (200 mL). The mixture was filtered and thesolid was slurried with hexanes (2×400 mL) and the filtrate was driedunder vacuum to give2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(trifluoromethyl)benzamide(9a) (13.1 g, 70%) as a solid. ESI-MS m/z calc. 406.09, found 407.5(M+1)⁺; Retention time: 1.73 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d₆) δ 11.28 (s, 1H), 10.63 (s, 1H), 7.84 (d, J=7.8 Hz, 1H), 7.60(d, J=7.1 Hz, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.26-7.20 (m, 1H), 7.14-7.06(m, 2H), 7.00-6.95 (m, 1H), 6.75 (d, J=1.8 Hz, 1H), 6.38 (dd, J=7.2, 2.1Hz, 1H), 2.16 (s, 3H) ppm.

Example 7 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(4a)

Cs₂CO₃ (651.6 mg, 2.0 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(60.0 mg, 0.2 mmol) and 4-fluoro-3-methoxyphenol (228 μl, 2.0 mmol) inDMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (10-99%) and HCl as a modifier toyield2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide(4a) (67.9 mg, 80%). ESI-MS m/z calc. 422.09, found 423.2 (M+1)⁺;Retention time: 1.56 minutes (3 minutes run).

Following a similar procedure as described above for parent compound 4a,the following compounds were prepared from2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 18a 2-(4-fluorophenoxy)-N-(2-oxo-4-fluorophenol 1,2-dihydropyridin-4-yl)-5- (trifluoromethyl)benzamide15a N-(2-oxo-1,2-dihydropyridin- 2-methylphenol 4-yl)-2-(o-tolyloxy)-5-(trifluoromethyl)benzamide 11a 2-(2-chloro-4-fluorophenoxy)-N-2-chloro-4-fluoro-phenol (2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide 10a 2-(4-fluoro-2-methylphenoxy)-N-4-fluoro-2-methyl-phenol (2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide  8a N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethoxy)phenol 2-(4-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide 17a N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(trifluoromethoxy)phenol 2-(2-(trifluoromethoxy)phenoxy)-5-(trifluoromethyl)benzamide

Example 8 Preparation of5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(7a)

Cs₂CO₃ (879.9 mg, 2.7 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-chlorobenzamide (72.0 mg,0.27 mmol) and 4-fluoro-3-methoxyphenol (307.7 μl, 2.7 mmol) in DMF (1mL) and the reaction was stirred at 100° C. for 1 hour. The reaction wasfiltered and purified by reverse phase HPLC using a gradient ofacetonitrile in water (10-99%) and HCl as a modifier to yield5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(7a) (31.8 mg, 30%). ESI-MS m/z calc. 388.06, found 389.10 (M+1)⁺;Retention time: 1.52 minutes (3 minutes run).

Following a similar procedure as described above for parent compound 7a,the following compounds were prepared from5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamideand the following alcohols.

Cmpd No. Product Alcohol 12a 5-chloro-2-(4-fluoro-2-4-fluoro-2-methyl-phenol methylphenoxy)-N-(2- oxo-1,2-dihydropyridin-4-yl)benzamide 14a 5-chloro-2-(2-chloro-4- 2-chloro-4-fluoro-phenolfluorophenoxy)-N-(2- oxo-1,2-dihydropyridin- 4-yl)benzamide

Example 9 Preparation of4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(1a)

Cs₂CO₃ (97.7 mg, 0.3 mmol) was added to a solution of4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (30.1mg, 0.1 mmol) and 4-fluoro-3-methoxyphenol (42.6 mg, 0.3 mmol) in NMP(0.5 mL) and the reaction was stirred at 90° C. for 2 hours. Thereaction was filtered and purified by reverse phase HPLC using agradient of acetonitrile in water (1-99%) and HCl as a modifier to yield4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(1a) (13.2 mg, 30%). ESI-MS m/z calc. 422.02, found 423.3 (M+1)⁺;Retention time: 1.57 minutes (3 minutes run).

Following a similar procedure as described above for parent compound 1a,the following compounds were prepared from4,5-dichloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide and thefollowing alcohols.

Cmpd No. Product Alcohol 3a 4,5-dichloro-2-(4-fluorophenoxy)-N-(2-oxo-4-fluorophenol 1,2-dihydropyridin-4-yl)benzamide

Example 10 Preparation of2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide(2a)

Cs₂CO₃ (69.8 mg, 0.21 mmol) was added to a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide(25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μL, 0.2 mmol) inNMP (0.3 mL) and the reaction was stirred at 100° C. for 45 minutes. Thereaction mixture was poured into water:ethyl acetate (9:1). The mixturewas shaken, and the solid was filtered off, washed with ether, thentriturated with ethyl acetate and dried to give the desired product. Themother liquors were filtered and washed with ethyl acetate to give asecond crop of material. Both solids were combined and dried undervacuum to give2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(2a) (15.4 mg, 45%) as a white solid. ESI-MS m/z calc. 472.08, found473.3 (M+1)+; Retention time: 1.62 minutes. ¹H NMR (400 MHz, DMSO-d₆) δ11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz,1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11.3,5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73(s, 3H) ppm.

Example 11 Preparation of4-chloro-2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide(13a)

To a solution of 4-chloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide(500 mg, 1.87 mmol) in NMP (5 mL) was added 4-fluoro-2-methyl-phenol(709.5 mg, 5.62 mmol) and Cs₂CO₃ (1.83 g, 5.62 mmol) and the reactionmixture was stirred at 90° C. for 2 hours. The reaction mixture waspoured into water and extracted with ethyl acetate (3×). The organicswere combined, washed with 3N NaOH (3×), water, brine, dried (Na₂SO₄)and evaporated to dryness. Purification by silica gel columnchromatography gave4-chloro-2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide(13a) (300 mg, 43%) as a tan solid. ESI-MS m/z calc. 372.07, found 373.1(M+1)⁺; Retention time: 1.5 minutes (3 minutes run). ¹H NMR (400 MHz,DMSO-d₆) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.30(dd, J=7.9, 1.6 Hz, 2H), 7.21 (d, J=8.7 Hz, 1H), 7.09 (d, J=5.5 Hz, 2H),6.75 (dd, J=5.1, 1.8 Hz, 2H), 6.38 (dd, J=7.2, 2.0 Hz, 1H), 2.16 (s, 3H)ppm.

Example 12 Preparation of2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(16a)

To a solution of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(30 mg, 0.1 mmol) in DMF (1 mL) was added 2,4-difluorophenol (130 mg,1.0 mmol) and Cs₂CO₃ (325.8 m g, 1.0 mmol) and the reaction mixture wasstirred at 100° C. for 1 hour. The reaction was cooled to 25° C.,filtered and purified by reverse phase chromatography using a gradientof acetonitrile in water (10-99%) and HCl as a modifier to yield2-(2,4-difluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(16). ESI-MS m/z calc. 410.07, found 411.2 (M+1)+; Retention time: 1.55minutes (3 minutes run).

Example 13 Preparation ofN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide(20)

A solution of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a) (406.3 mg, 1.0 mmol) and chloromethyl chloroformate (106.7 μL, 1.2mmol) in dichloromethane (3.5 mL) and N,N-dimethylformamide (0.3 mL) wasstirred at room temperature for 4 hours. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous sodiumbicarbonate, brine, dried with Na₂SO₄, filtered and evaporated todryness to giveN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamidethat was used in the next step without further purification. ESI-MS m/zcalc. 454.07, found 455 (M+1)⁺; Retention time: 0.73 minutes (1 minuterun).

The crudeN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamidefrom the previous step was taken up in N,N-dimethylformamide (5 mL).Di-tert-butoxyphosphoryloxypotassium (496.6 mg, 2.0 mmol) andtetrabutylammonium iodide (36.94 mg, 0.10 mmol) were added and thereaction mixture was stirred at 70° C. for 4 hours. The reaction mixturewas then diluted with ethyl acetate and washed with water then brine,dried with Na₂SO₄, filtered and evaporated to dryness. The material waspurified by column chromatography (40 g silica, 50-100% EtOAc inHexanes), fractions with the product were pooled and evaporated to givedi-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (20) (280 mg, 45%) as a yellow oil that was used in the nextstep without further purification. ESI-MS m/z calc. 628.20, found 629(M+1)⁺; Retention time: 0.76 minutes (1 minute run).

Example 14 Preparation of[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9)

A solution of di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (20) (50 mg, 0.080 mmol) in acetonitrile (1 mL), H₂O (1 mL),and acetic acid (1 mL) was stirred at 70° C. for 3 hours then evaporatedto dryness. The material was then co-evaporated with acetonitrile (3×),triturated with acetonitrile, filtered, washed with acetonitrile anddesiccated to give[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9) (20 mg, 49%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.49 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.61(d, J=7.6 Hz, 2H), 7.27-7.19 (m, 1H), 7.11 (dd, J=10.9, 7.6 Hz, 2H),6.98 (s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1 Hz, 1H), 5.53(d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. ³¹P NMR (162 MHz, DMSO-d₆−85% H₃PO₄aq. as internal standard−0 ppm) 6-1.76 (t, J=9.6 Hz, 1H).

The material was further purified according to the following procedure.To a stirred suspension of[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9) (30.00 mg, 0.05810 mmol) in isopropanol (600.0μL) was added methanol (300.0 μL) which caused the material to go intosolution. NaOH (14.52 μL of 4 M, 0.058 mmol) was added which caused awhite precipitate and the mixture was stirred at room temperature for 30minutes. The reaction mixture was then cooled to 0° C., filtered, washedwith cooled isopropanol and dried under vacuum to give[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9) as a white solid. ESI-MS m/z calc. 516.07,found 517.0 (M+1)+; Retention time: 0.57 minutes (1 min UPLC run).

Example 15 Alternate preparation of[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9)

A sample of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidemonohydrate (9a) (6.0 g, 14.7 mmol) was dehydrated under vacuum at 65°C. A solution of anhydrous2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a) (5.0 g, 12.31 mmol) and N,N-dimethylformamide (10.0 mL) indichloromethane (50.0 mL) was stirred at room temp., chloromethylchloroformate (1.64 ml, 18.46 mmol) was added and the solution wasstirred at room temperature for one hour. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous sodiumbicarbonate, brine, dried with anhydrous sodium sulfate, filtered andevaporated to dryness. The resulting oil was purified by columnchromatography (40 g silica, 20-100% EtOAc in Hexanes), productfractions were pooled and evaporated to giveN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide(3.26 g, 7.168 mmol) that was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 7.86 (d, J=7.8Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H),7.10 (dd, J=7.7, 2.0 Hz, 2H), 6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50(dd, J=7.6, 2.3 Hz, 1H), 5.79 (s, 2H), 2.16 (s, 3H) ppm.

A mixture ofN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide(500 mg, 1.1 mmol), di-tert-butoxyphosphoryloxy potassium (409.2 mg,1.65 mmol), tetrabutylammonium iodide (20.3 mg, 0.05 mmol) anddiisopropylethyl amine (191.4 ul, 1.1 mmol) in acetonitrile (10.0 ml)were stirred at 70° C. for one hour. The reaction mixture was thendiluted with ethyl acetate and washed with water and brine and theorganic layer was evaporated to dryness. The crude material was purifiedby column chromatography (4 g silica, 25-100% EtOAc in Hexanes), productfractions were pooled and evaporated to give di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (20) (390 mg, 56%) as a light amber solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.83 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.76 (d, J=7.6 Hz,1H), 7.66-7.58 (m, 1H), 7.28-7.19 (m, 1H), 7.10 (dd, J=7.7, 2.0 Hz, 2H),6.98 (s, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.50 (dd, J=7.6, 2.3 Hz, 1H), 5.79(s, 2H), 2.16 (s, 3H) ppm.

A solution of di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (20) (350 mg, 0.557 mmol) in acetonitrile (7 mL), acetic acid(7 mL), and H₂O (7 mL) was stirred at 70° C. and the deprotectionreaction followed by HPLC. Deprotection was complete after 1.5 hours.The reaction mixture was partially concentrated to remove the bulk ofthe acetonitrile then toluene (100 ml) was added and the mixtureevaporated to azeotropically remove water and acetic acid. To theresulting suspension was added heptane (10 ml) and the suspensiondistilled down to 2-3 volumes (1 ml). Heptane (2 ml) was added and thesuspension further stirred at room temp and filtered. The collectedsolid was dried in vacuo to afford[4-[[2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (9) (254 mg, 88.4%) as off-white crystalline solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 2H), 10.77 (s, 1H), 7.86 (d, J=8.0Hz, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.26-7.19 (m, 1H), 7.09 (dd, J=10.9,7.6 Hz, 2H), 6.98 (s, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.43 (dd, J=7.5, 2.1Hz, 1H), 5.53 (d, J=9.7 Hz, 2H), 2.16 (s, 3H) ppm. ³¹P NMR (162 MHz,DMSO-d₆) δ−2.35 (t, J=9.6 Hz, 1H) ppm.

Example 15A Preparation of2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide

A 50 liter jacketed glass reactor was fitted with an N₂ inlet, amechanical stirrer, and a condenser. With the stirrer set to 150 rpm andthe jacket temperature set at 40° C., 2-Me-THF (6.000 L, 3.0 vol),2-fluoro-4-(trifluoromethyl)benzoic acid (2000 g, 9.610 mol),2-methoxypyridin-4-amine (1.278 kg, 10.09 mol), and TEA (2.917 kg, 4.018L, 28.83 mol) were added to the reactor, which resulted in a slightlyhazy, light amber solution. The reactor was switched to reaction controland heated to 35° C. To the solution was added T3P in 2-Me-THF (9.176kg, 9.176 L of 50% w/w, 14.42 mol) over 30-45 min, which resulted in alight amber solution. After 2 hours, the reaction was judged to becomplete by HPLC analysis (<2% of 1 remaining). The reaction wasquenched with water (1.000 L, 0.5 vol), which was added via additionfunnel over a period of 10 minutes in order to control the exothermicquenching reaction. The mixture was then diluted with 2-Me-THF (8.000 L,4.0 vol) and water (8.000 L, 4.0 vol) and stirred for 30 minutes at30-40° C. After stirring was stopped, the layers were allowed toseparate, and the aqueous layer was removed. The organic layer waswashed with 10% aqueous NaOH (6.000 L, 3.0 vol), stirring resulted in anemulsion. Brine (500.0 mL, 0.25 vol) was added, and the mixture wasstirred for about 5 minutes. The layers were separated, and the aqueouslayer removed. The organic layer was washed again with brine (10.00 L,5.0 vol), and the aqueous layer was drained. The organic layer was driedover Na₂SO₄, and filtered through diatomaceous earth (Celite). Thefilter cake was washed with 2-Me-THF (4.000 L, 2.0 vol) and pulled dry.The filtrate was transferred to a rotovap, and partial distillation ofsolvent was begun at a bath temperature of 40° C. and a pressure of 150mbar, resulting in the formation of solids in the mixture. Cyclohexane(10.00 L, 5.0 vol) was added portionwise during the partialdistillation. Distillation was stopped, the reaction mixture (˜8 liter)was slurried on the rotovap, and the bath temperature was reduced toroom temperature. The mixture was filtered, and the filter cake waswashed with cyclohexane (2.000 L, 1.0 vol) and pulled dry under anitrogen blanket to afford a light yellow solid. The solid was scoopedout of the funnel and dried in vacuo (40° C., <30 mbar, rotovap) toafford 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide(2,501 g, 7.959 mol, 83%) as a fine, off-white solid.

Example 15B Preparation of2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidehydrobromide

To a 50 liter jacketed glass reactor fitted with an N₂ inlet and amechanical stirrer set was added AcOH (17.50 L, 7.0 vol) and2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide (2500 g,7.956 mol), and the resulting mixture was stirred. A solution of HBr inHOAc (5.853 kg, 3.928 L of 33% w/w, 23.87 mol) was added, resulting in amild exotherm and a light amber solution. The solution became a darkeramber color as more HBr was added. The temperature of the reactionmixture was increased to a mild reflux (70° C. internal), over 30 min,resulting in the generation of a substantial amount of gas (MeBr, HBr).The internal temperature of the reaction mixture was then increased to85° C. over 1.5 hrs, and stirring was continued overnight at atemperature of 85° C. The progress of the reaction was monitored by HPLCanalysis until completion, which was achieved after about 16 hours (<1%of 2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamideremaining relative to the product2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidehydrobromide). The internal temperature of the reaction mixture wasreduced from 85 to 50° C. over 30 min, and then toluene (7.500 L, 3.0vol) was added. Stirring was continued for 10-15 min. The internaltemperature of the reaction mixture was then reduced to 20° C., and themixture was stirred at this temperature for 1-2 hrs. The reactionmixture was then filtered, and the wet filter cake was washed withtoluene (7.500 L, 3.0 vol) and pulled dry. The solid material wasscooped out of the filter and dried in vacuo (40° C., 10-25 mbar,rotovap) to afford2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidehydrobromide (2609 g, 6.846 mol, 86%) as white, crystalline solid.

Example 15C Preparation of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a)

To a 50 liter jacketed glass reactor fitted with an N₂ inlet and amechanical stirrer was added 1-methyl-2-pyrrolidinone (NMP) (3.75liters). The solution was stirred,2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamidehydrobromide salt (1500.2 g, 3.94 moles, 1.0 eq) was added and chasedwith NMP (1 liter), and the jacket temperature was adjusted to 35° C.Potassium carbonate (1631.9 g, 11.8 moles, 3.0 eq, 325 mesh) was thenadded portionwise over 10 minutes, during which time the reactiontemperature increased to 40° C. The resulting suspension was treatedwith a solution of 4-fluoro-2-methylphenol (5, 546.1 g, 4.33 moles, 1.1eq, AK Scientific) in NMP (2.25 liters) with stirring, and the additionfunnel was then rinsed with NMP (0.75 liters) to give an orangesuspension. The jacket temperature was raised to 61° C. over 30 minutesand the suspension was stirred overnight under nitrogen, at which timethe reaction was judged to be complete by HPLC analysis. To the reactionmixture was added 2-methyltetrahydrofuran (15 liters) and water (15liters) and the mixture stirred until all solids dissolved. Stirring wasstopped, the orange aqueous layer drained off, and the organic layerwashed with water (7.5 liters) while stirring and a jacket temperatureof 52° C.). The aqueous wash procedure was repeated 4 times (3×7.5 literwater washes, then 1×4.5 liter water wash). The resulting organic slurrywas stirred at a jacket temperature of 50.8° C., and isopropyl acetate(6 liters, Sigma Aldrich) was added. The jacket temperature was rampeddown to 20° C. over 30 minutes, and the slurry was stirred overnightbefore collecting the precipitated solid by filtration. The collectedsolid was returned to the reactor, slurried in isopropyl acetate withstirring for about 2 hours, then filtered, rinsed with isopropyl acetate(1.5 liters) and dried in vacuo at 65° C. to give 1253.1 g (78%) of2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a) as an off-white solid.

Example 15D Preparation ofN-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide

To a 50 liter jacketed glass reactor fitted with an N₂ inlet and amechanical stirrer, and with a jacket temperature set at 20° C., wasadded2-(4-fluoro-2-methylphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide(9a, 2482.0 g, 6.11 moles, 1.0 eq) under nitrogen. Ethyl acetate (25liters) was added with stirring at 100 rpm followed by 1,4-diazabicyclo[2.2.2] octane (DABCO) (342.6 g, 3.05 moles, 0.5 eq) and DMF (1.25liters, Sigma-Aldrich). Chloromethyl chloroformate (815 ml, 9.16 moles,1.5 eq) was then added over 30 minutes. When the addition ofchloromethyl chloroformate was complete, the jacket temperature wasramped up to 60° C. over 30 minutes. The resulting yellow-slurry wasstirred for 3 hours at about 60° C., at which time the reaction wasjudged to be complete by HPLC analysis. The jacket temperature wasramped down to 15° C. over 20 minutes before quenching the reaction byslow addition of water (500 ml) over 10 minutes. Additional water wasadded, and the mixture stirred at 115 rpm for 15 minutes. Stirring wasstopped, the aqueous layer was discarded, and the organic layer washedwith water (5 liters), followed by a saturated solution of NaHCO₃ (137g) in water (620 ml). The organic layer was seeded with 5 g ofN-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide(7), and the resulting slurry was partially concentrated (removed 18.5liters of organics) in the rotovap (40° C., vacuum). The resultingsuspension was stored at room temperature under nitrogen atmosphereovernight, during which time additional material crystallized out ofsolution. The remaining solvent was chased with heptanes adding moreheptanes as needed to maintain the volume at 10 liters. The thicksuspension was stirred on the rotovap at room temperature for 45minutes, and then the solids were collected by filtration. The off-whitesolid was washed with heptanes (2.5 liters), then dried in vacuo (40°C., full house vacuum) to give 2409 g (87%) ofN-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamideas an off-white crystalline solid.

Example 15E Preparation of di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (20)

To a 50 liter jacketed glass reactor fitted with an N₂ inlet and amechanical stirrer, and with a jacket temperature set at 41° C., wasaddedN-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide(1199.5 g, 2.64 moles, 1.0 eq) under nitrogen. Ethyl acetate (12 liters)was added with stirring to produce a suspension. To the mixture wasadded potassium di-tert-butylphosphate (792.7 g @ 95% purity, 3.03moles, 1.15 eq), then TBAI (9.7 g, 0.026 moles, 0.01 eq), and the jackettemperature was ramped to 71° C. over 20 minutes. The resultinggelatinous suspension was stirred for 4.5 hours at which point HPLCanalysis indicated that the reaction was complete. The jackettemperature was ramped to 30° C. over 15 minutes, and then water (6liters) was added with stirring. The aqueous layer was drained off, andthen the organic layer was washed twice with water (1×3.6 liters, then1×2.4 liters). The organic layer was concentrated down to 3.0-3.5volumes at 40° C. using a rotovap. Heptane (1.8 liters) was added as anantisolvent, and then the bath heater of the rotovap was turned off, andthe mixture was allowed to cool to room temp and was stirred at 40 rpmovernight. The solids were collected by filtration, rinsed with heptanes(1.2 liters), and then dried in vacuo at 45° C. to give 1417.7 g (88%)of di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (20) as a crystalline, light amber solid.

Example 15F Preparation of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate (9)

To a 72 liter jacketed glass reactor fitted with an N₂ inlet and amechanical stirrer, and with a jacket temperature set at 40° C., wasadded di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl)phosphate (20, 2820.9 g, 4.49 moles, 1.0 eq) and isopropyl alcohol (25.4liters, 9.0 volumes). The mixture was stirred at 200 rpm, and aceticacid (14.1 liters, 5.0 volumes) was added, resulting in a clearsolution. The clear solution was polish filtered and transferred to a 50liter jacketed glass reactor system with stirring at 100 rpm. Water (5.6liters) was added, and the jacket temperature was ramped to 71° C. over20 minutes. After 4.5 hours of stirring and heating, HPLC analysisindicated that the reaction was complete. The jacket temperature wasramped down to 19° C. over 3 hours, and the product began crystallizingout of solution. The solid was collected by filtration, rinsed withacetone (5 liters). The solid was added back into the reactor vessel,acetone was added (8.5 liters), the jacket temperature was ramped to 45°C. over 10 minutes, and the suspension was stirred. After 40 minutes,the jacket temperature was ramped to 20° C. over 30 minutes, and thecrystalline solid was collected by filtration, rinsed with acetone (5liters) and dried in vacuo at 50° C. to give 1917.7 g (83%) of(4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyldihydrogen phosphate (9) as a crystalline white solid.

Example 15G Preparation ofN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide(21)

A solution of2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide(2a) (99.9 mg, 0.2115 mmol) and chloromethyl chloroformate (32.73 mg,22.04 μL, 0.2538 mmol) in DCM (900 μL) and DMF (100 μL) was stirred atroom temperature for 4 hours (gas evolved). The reaction mixture wasdiluted with EtOAc, the organic phase washed with sat. aq. NaHCO₃,brine, dried with Na₂SO₄ and evaporated to dryness. The residue wastaken up in DMF (999 μL), di-tert-butoxyphosphoryloxypotassium (105.0mg, 0.4230 mmol) and tetrabutylammonium iodide (7.81 mg, 0.021 mmol)were added and the reaction mixture was stirred at 70° C. for 4 hours.The reaction mixture was cooled, diluted with water and extracted withEtOAc (3×). The organics were combined, washed with water then brine,dried with Na₂SO₄ and evaporated to dryness. Purification by columnchromatography (4 g silica; 0-100% EtOAc in hexanes) gave di-tert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (21) (35 mg, 0.05039 mmol, 23.8%) as a clear oil. ESI-MS m/zcalc. 694.18787, found 695.4 (M+1)+; Retention time: 0.78.

Example 15H Preparation ofN-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide(2)

A solution of ditert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (21) (35 mg, 0.05039 mmol) in CH₃CN (700.0 μL), water (700.0μL) and AcOH (700.0 μL) was refluxed for 1 hour then evaporated todryness. The material was then co-evaporated with CH₃CN (3×), trituratedwith CH₃CN, filtered, washed with CH₃CN and desiccated to give[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (2) (13 mg, 0.02210 mmol, 43.9%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.63(d, J=7.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 7.31 (dd, J=8.9, 5.9 Hz, 1H),7.16 (dd, J=10.7, 2.9 Hz, 1H), 6.94 (d, J=1.9 Hz, 1H), 6.91-6.84 (m,1H), 6.77 (s, 1H), 6.47 (dd, J=7.6, 2.2 Hz, 1H), 5.54 (d, J=9.7 Hz, 2H),3.74 (s, 3H) ppm. ³¹P NMR (162 MHz, DMSO-d₆−85% H₃PO₄ aq. as internalstandard−0 ppm) 6-1.93 (t, J=9.7 Hz, 1H) ppm.

Example 151 Di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (22)

A solution of2-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide(18a) (98 mg, 0.2498 mmol) and chloromethyl chloroformate (38.66 mg,26.39 μL, 0.2998 mmol) in CH₂Cl₂ (1 mL) and DMF (100 μL) was stirred atroom temperature for 4 hours (gas evolved). The reaction mixture wasdiluted with EtOAc and the organic phase washed with sat. aq. NaHCO₃,brine, dried with Na₂SO₄ and evaporated to dryness. The residue wastaken up in DMF (1 mL), di-tert-butoxyphosphoryloxypotassium (124.0 mg,0.4996 mmol) and tetrabutylammonium iodide (9.227 mg, 0.02498 mmol) wereadded and the reaction mixture was stirred at 70° C. for 4 hours. Thereaction mixture was cooled, diluted with water and extracted with EtOAc(3×). The organic layers were combined, washed with water then brine,dried with Na₂SO₄ and evaporated to dryness. Purification by columnchromatography (4 g silica; 0-100% EtOAc in Hx) gave di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (22) (67 mg, 0.1090 mmol, 43.7%) as a clear oil. ESI-MS m/zcalc. 614.1805, found 615.5 (M+1)+; Retention time: 0.73 minutes.

Example 15J[4-[[2-(4-Fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (18)

A solution of di-tert-butyl[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (22) (67 mg, 0.1090 mmol) in CH₃CN (1.340 mL), water (1.340mL) and AcOH (1.340 mL) was refluxed for 1 hour then evaporated todryness. The material was then co-evaporated with CH₃CN (3×), trituratedwith CH₃CN, filtered, washed with CH₃CN and desiccated to give[4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (18) (32 mg, 0.06052 mmol, 55.5%) as a white solid.ESI-MS m/z calc. 502.0553, found 503.4 (M+1)+; Retention time: 1.39minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.70 (s, 1H), 8.00 (d, J=2.4 Hz,1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.35-7.23 (m,4H), 7.00 (d, J=8.7 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.45 (dd, J=7.6,2.3 Hz, 1H), 5.53 (d, J=9.7 Hz, 2H) ppm. ³¹P NMR (162 MHz, DMSO-d₆−85%H₃PO₄ aq. as internal standard−0 ppm) δ−2.11 (t, J=9.6 Hz) ppm.

Example 15K Di-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (23)

A solution of4-chloro-2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide(13a) (99 mg, 0.2656 mmol) and chloromethyl chloroformate (82.19 mg,55.35 μL, 0.6374 mmol) in THF (2 mL) was added DMF (0.2 mL) and CH₂Cl₂(0.5 mL) and was stirred at room temperature for 2 hours. The reactionmixture was diluted with EtOAc and the organic phase washed with sat.aq. NaHCO₃, brine, dried with Na₂SO₄ and evaporated to dryness. Theresidue was taken up in DMF (1 mL), di-tert-butoxyphosphoryloxypotassium(263.7 mg, 1.062 mmol) and tetrabutylammonium iodide (9.810 mg, 0.02656mmol) were added and the reaction mixture was stirred at 70° C. for 4hours. The reaction mixture was cooled, diluted with water and extractedwith EtOAc (3×). The organic phases were combined, washed with waterthen brine, dried with Na₂SO₄ and evaporated to dryness. Purification bycolumn chromatography (12 g silica; 0-100% EtOAc in Hx) gavedi-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (23) (35 mg, 0.05882 mmol, 22.2%) as a clear foam. ESI-MS m/zcalc. 594.1698, found 595.5 (M+1)+; Retention time: 0.77 minutes.

Example 15L[4-[[4-Chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (13)

A solution of di-tert-butyl[4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (23) (35 mg, 0.05882 mmol) in CH₃CN (700.0 μL), water (700.0μL) and AcOH (0.7 mL, 12.31 mmol) was heated at 90° C. for 20 min thenevaporated and co-evaporated with CH₃CN (3×). The material wastriturated with CH₃CN, filtered, washed with CH₃CN and desiccated togive[4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (13) (13 mg, 0.02558 mmol, 43.5%) as a white solid.ESI-MS m/z calc. 482.0446, found 483.4 (M+1)+; Retention time: 1.41minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 7.66 (d, J=8.2 Hz,1H), 7.60 (d, J=7.5 Hz, 1H), 7.30 (dd, J=8.2, 2.0 Hz, 1H), 7.21 (d,J=9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J=2.3 Hz, 1H), 6.74 (d, J=2.0Hz, 1H), 6.44 (dd, J=7.6, 2.3 Hz, 1H), 5.51 (d, J=9.7 Hz, 2H), 2.16 (s,3H) ppm. ³¹P NMR (162 MHz, DMSO-d₆-85% H₃PO₄ aq. as internal standard−0ppm) δ−2.15 (t, J=9.7 Hz) ppm.

Example 15M Di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (24)

To a solution of2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide(10a) (102 mg, 0.2510 mmol) and chloromethyl chloroformate (77.67 mg,52.30 μL, 0.6024 mmol) in CH₂Cl₂ (2 mL) was added DMF (200 μL) and thereaction mixture was stirred at room temperature for 1 hour. At thistime, more chloromethyl chloroformate (77.67 mg, 52.30 μL, 0.6024 mmol)was added and the reaction mixture was heated to 70° C. for 25 min. Thereaction mixture was diluted with EtOAc, the organic phase washed withsat. aq. NaHCO₃, brine, dried with Na₂SO₄ and evaporated to dryness. Theresidue was taken up in DMF (3 mL), di-tert-butoxyphosphoryloxypotassium(249.3 mg, 1.004 mmol) and tetrabutylammonium iodide (9.271 mg, 0.02510mmol) were added and the reaction mixture was stirred at 70° C. for 4hours. The reaction mixture was cooled, diluted with water and extractedwith EtOAc (3×). The organic layers were combined, washed with waterthen brine, dried with Na₂SO₄ and evaporated to dryness. Purification bycolumn chromatography (12 g silica; 0-100% EtOAc in Hx) gavedi-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (24) (23 mg, 0.03659 mmol, 14.6%) as a clear glass. ESI-MS m/zcalc. 628.19617, found 629.5 (M+1)+; Retention time: 0.78 minutes.

Example 15N[4-[[2-(4-Fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (10)

A solution of di-tert-butyl[4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (24) (23 mg, 0.03659 mmol) in CH₃CN (460.0 μL), water (460.0μL) and AcOH (460.0 μL) was heated at 90° C. for 15 min then evaporatedand co-evaporated with CH₃CN (3×). The material was triturated withCH₃CN, filtered, washed with CH₃CN and desiccated to give[4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (10) (6 mg, 0.01104 mmol, 30.2%) as a white solid.ESI-MS m/z calc. 516.0709, found 517.4 (M+1)+; Retention time: 1.45minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.42 (d, J=2.4 Hz,1H), 8.22 (dd, J=8.8, 2.2 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.67 (dd,J=9.5, 3.1 Hz, 1H), 7.65-7.50 (m, 2H), 7.35 (d, J=2.3 Hz, 1H), 7.26 (d,J=8.7 Hz, 1H), 6.88 (dd, J=7.6, 2.4 Hz, 1H), 5.95 (d, J=9.8 Hz, 2H),2.57 (s, 3H) ppm. ³¹P NMR (162 MHz, DMSO-d₆−85% H₃PO₄ aq. as internalstandard−0 ppm) δ−2.17 (t, J=9.7 Hz) ppm.

Example 15O Di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (25)

To a solution of4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide(1a) (101 mg, 0.2386 mmol) and chloromethyl chloroformate (36.92 mg,24.86 μL, 0.2863 mmol) in CH₂Cl₂ (2 mL) was added DMF (200 μL) and thereaction mixture was stirred at room temperature for 1 hour. At thistime, THF (1 mL) was added followed by more chloromethyl chloroformate(36.92 mg, 24.86 μL, 0.2863 mmol) and the reaction mixture stirred atroom temperature for 1 h. More DMF (1 mL) and chloromethyl chloroformate(36.92 mg, 24.86 μL, 0.2863 mmol) was added and the reaction mixture washeated to 70° C. for 15 min. The reaction mixture was diluted with EtOAcand the organic phase washed with sat. aq. NaHCO₃, brine, dried withNa₂SO₄ and evaporated to dryness. The residue was taken up in DMF (1.010mL), di-tert-butoxyphosphoryloxypotassium (118.5 mg, 0.4772 mmol) andtetrabutylammonium iodide (8.813 mg, 0.02386 mmol) was added and thereaction mixture stirred at 70° C. for 4 h. The reaction mixture wascooled, diluted with water and extracted with EtOAc (3×). The organiclayers were combined, washed with water then brine, dried with Na₂SO₄and evaporated to dryness. Purification by column chromatography (12 gsilica; 0-100% EtOAc in Hx) gave di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (25) (40 mg, 0.06197 mmol, 26.0%) as a clear glass. ESI-MS m/zcalc. 644.12573, found 647.3 (M+1)+; Retention time: 0.81 minutes.

Example 15P[4-[[4,5-Dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (1)

A solution of di-tert-butyl[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methylphosphate (40 mg, 0.06197 mmol) in CH₃CN (800.0 μL), water (800.0 μL)and AcOH (800 μL, 14.07 mmol) was heated at 90° C. for 15 min thenevaporated and co-evaporated with CH₃CN (3×). The material wastriturated with CH₃CN, filtered, washed with CH₃CN and desiccated togive[4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyldihydrogen phosphate (1) (19 mg, 0.03385 mmol, 54.6%) as a white solid.ESI-MS m/z calc. 532.00055, found 533.3 (M+1)+; Retention time: 1.5minutes. ¹H NMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.91 (s, 1H), 7.62(d, J=7.6 Hz, 1H), 7.27 (dd, J=8.9, 5.8 Hz, 1H), 7.13 (dd, J=10.7, 3.0Hz, 1H), 6.90 (d, J=2.3 Hz, 1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44(dd, J=7.6, 2.4 Hz, 1H), 5.52 (d, J=9.7 Hz, 2H), 3.76 (s, 3H) ppm. ³¹PNMR (162 MHz, DMSO-d₆−85% H₃PO₄ aq. as internal standard−0 ppm) δ−2.12(t, J=9.4 Hz) ppm.

Compounds 3-8, 11, 12 and 14-17 may be prepared using similar proceduresas described above for preparing compounds 1, 2, 9, 10, 13 and 18.

Example 15Q

A spray dry dispersion of compound 9 with 50% HPMCAS was prepared asfollows. Compound 9 (14 grams) was added to a beaker (1000 ml), followedby 400 mL of THF/H₂O (95:5) and 100 mL of MeOH. The material was stirredfor 1 h giving a slightly hazy solution. In a separate container, 14grams of Hydroxypropylmethylcellulose acetate succinate HF grade(HPMCAS-HF) was dissolved in 100 mL of THF and the mixture was stirredfor 15 minutes. The two solutions were combined and stirred continuouslywhile spray drying using a Buchi Mini Spray Dryer with the followingparameters:

T inlet (setpoint) 78° C. T outlet (start) 38° C. T outlet (end) 35° C.Nitrogen Pressure 75 psi Aspirator 100%  Pump 20% Rotometer 60 mm FilterPressure −50 mbar Condenser Temp −5° C. Run Time 3 h

Approximately 18.2 g of compound 9 amorphous Form C as a spray drydispersion (65% yield) was recovered. The amorphous Form C of compound 9in the spray dry dispersion was confirmed by XRPD (FIG. 5) and DSC,showing a glass transition temperature of 96° C.

A neat amorphous Form C of compound 9 was prepared by spray drydispersion according to the conditions discussed above except that noHPMCAS polymer was added. The neat amorphous Form C of compound 9 in thespray dry dispersion was confirmed by XRPD (FIG. 6).

The structure of crystalline Form B of compound 9 was confirmed bysingle-crystal x-ray diffraction analysis (FIG. 1). Single crystaldiffraction data was acquired on a Bruker Apex II diffractometerequipped with sealed tube Cu K-alpha source (Cu Kα radiation, γ=1.54178Å) and an Apex II CCD detector. A colorless plate shaped crystal withdimensions of 0.01×0.05×0.05 mm was selected for data collection. Threebatches of 40 frames separated in reciprocal space were obtained toprovide an orientation matrix and initial cell parameters. Final cellparameters were obtained and refined after data collection was completedbased on the full data set.

A diffraction data set of reciprocal space was obtained to a resolutionof 0.84 Å using 1.0° steps using 60 seconds exposures for each low angleframe and 120 seconds for each high angle frame. Observation of thecrystal after data collection showed no signs of decomposition.

The data was collected, refined and reduced using the Bruker Apexsoftware. The structure was solved using the SHELXS97 (Sheldrick, 1990);program(s) and the structure refined using the SHELXL97 (Sheldrick,1997) program. The crystal shows monoclinic cell with P2₁/c space group.The lattice parameters are a=20.194(9)Å, b=9.205(4)Å, c=11.956(5)Å,β=95.213(8°). Volume=2213.4(17)Å³. The high angle reflections were weak,leading to a high R factor 9.8%. However, the structure was ordered andthere was one symmetry independent molecule in the structure.

TABLE 3 Analytical data for Compounds and Intermediates LCMS Ret. Cmpd.Time in MS No. minutes (M + 1) ¹H-NMR (400 MHz) 1 1.50 533.3 (DMSO-d₆) δ10.58 (s, 1H), 7.91 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.27 (dd, J =8.9, 5.8 Hz, 1H), 7.13 (dd, J = 10.7, 3.0 Hz, 1H), 6.90 (d, J = 2.3 Hz,1H), 6.86 (s, 1H), 6.86-6.81 (m, 1H), 6.44 (dd, J = 7.6, 2.4 Hz, 1H),5.52 (d, J = 9.7 Hz, 2H), 3.76 (s, 3H) ppm  1a 1.57 423.3 (DMSO-d₆) δ11.27 (s, 1H), 10.49 (s, 1H), 7.90 (br s, 1H), 7.32 (d, J = 7.2 Hz, 1H),7.28 (dd, J = 8.9, 5.8 Hz, 1H), 7.14 (dd, J = 10.7, 2.9 Hz, 1H),6.89-6.82 (m, 2H), 6.77 (s, 1H), 6.39 (dd, J = 7.2, 2.1 Hz, 1H), 3.76(s, 3H) ppm 2 1.54 583.4 (DMSO-d₆) δ 10.72 (s, 1H), 7.85 (d, J = 8.0 Hz,1H), 7.63 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.31 (dd, J =8.9, 5.9 Hz, 1H), 7.16 (dd, J = 10.7, 2.9 Hz, 1H), 6.94 (d, J = 1.9 Hz,1H), 6.91-6.84 (m, 1H), 6.77 (s, 1H), 6.47 (dd, J = 7.6, 2.2 Hz, 1H),5.54 (d, J = 9.7 Hz, 2H), 3.74 (s, 3H) ppm  2a 1.62 473.3 (DMSO-d₆) δ11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.9Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J = 10.7, 2.8 Hz, 1H), 6.88 (dd, J= 11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J = 7.1 Hz,1H), 3.73 (s, 3H) ppm  3a 1.53 393.1 (DMSO-d₆) δ 11.32 (s, 1H), 10.57(s, 1H), 7.95 (s, 1H), 7.34-7.24 (m, 3H), 7.22-7.15 (m, 3H), 6.74 (s,1H), 6.38 (d, J = 7.2 Hz, 1H) ppm  4a 1.56 423.2  5a 1.8 459.5  6a 1.59443.5 (DMSO-d₆) δ 7.87 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H),7.37-7.25 (m, 3H), 7.24-7.16 (m, 2H), 7.07 (s, 1H), 6.73 (s, 1H), 6.37(d, J = 6.9 Hz, 1H) ppm  7a 1.52 389.1  8a 1.93 459.3 (DMSO-d₆) δ 11.29(s, 1H), 10.62 (s, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.86 (dd, J = 8.7, 2.4Hz, 1H), 7.58-7.40 (m, 2H), 7.40-7.21 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H),6.76 (d, J = 2.1 Hz, 1H), 6.38 (dd, J = 7.2, 2.1 Hz, 1H) ppm 9 1.79407.1 (DMSO-d₆) δ 11.27 (s, 1H), 10.63 (s, 1H), 7.84 (d, J = 7.8 Hz,1H), 7.60 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.23 (m, 1H),7.10 (m, 2H), 6.97 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.38 (dd, J = 7.2,2.0 Hz, 1H), 2.16 (s, 3H) ppm  9a 1.79 407.1 (DMSO-d₆) δ 11.27 (s, 1H),10.63 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.31(d, J = 7.2 Hz, 1H), 7.23 (m, 1H), 7.10 (m, 2H), 6.97 (s, 1H), 6.76 (d,J = 1.6 Hz, 1H), 6.38 (dd, J = 7.2, 2.0 Hz, 1H), 2.16 (s, 3H) ppm 10 1.45 517.4 (DMSO-d₆) δ 11.14 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.22(dd, J = 8.8, 2.2 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.67 (dd, J = 9.5,3.1 Hz, 1H), 7.65-7.50 (m, 2H), 7.35 (d, J = 2.3 Hz, 1H), 7.26 (d, J =8.7 Hz, 1H), 6.88 (dd, J = 7.6, 2.4 Hz, 1H), 5.95 (d, J = 9.8 Hz, 2H),2.57 (s, 3H) ppm 10a 1.6 407.2 (DMSO-d₆) δ 11.77 (s, 1H), 10.79 (s, 1H),8.00 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.8, 2.3 Hz, 1H), 7.45 (d, J =7.2 Hz, 1H), 7.25 (dd, J = 9.3, 3.0 Hz, 1H), 7.16 (m, 2H), 6.95 (d, J =1.9 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 6.56 (dd, J = 7.2, 2.0 Hz, 1H),2.14(s, 3H) ppm 11a 1.57 427.2 (DMSO-d₆) δ 11.29 (s, 1H), 10.62 (s, 1H),8.02 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.8, 2.2 Hz, 1H), 7.69 (dd, J =8.4, 3.0 Hz, 1H), 7.45 (dd, J = 9.1, 5.3 Hz, 1H), 7.40- 7.30 (m, 2H),6.92 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 1.9 Hz, 1H), 6.42 (dd, J = 7.2,2.1 Hz, 1H) ppm 12a 1.57 373.1 13  1.41 483.4 (DMSO-d₆) δ 10.59 (s, 1H),7.66 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.30 (dd, J = 8.2,2.0 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.16-7.05 (m, 2H), 6.89 (d, J =2.3 Hz, 1H), 6.74 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 7.6, 2.3 Hz, 1H),5.51 (d, J = 9.7 Hz, 2H), 2.16 (s, 3H) ppm. 13a 1.57 373.2 (DMSO-d₆) δ11.48 (s, 1H), 10.57 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.36 (d, J = 7.2Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.10(m, 2H), 6.83 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 6.45 (dd, J= 7.2, 2.1 Hz, 1H), 2.16 (s, 3H) ppm 14a 1.64 393.1 15a 1.48 359.2(DMSO-d₆) δ 11.25 (s, 1H), 10.48 (s, 1H), 7.65 (t, J = 8.5 Hz, 1H), 7.29(m, 4H), 7.19 (m, 2H), 6.91 (d, J = 1.9 Hz, 1H), 6.75 (d, J = 1.9 Hz,1H), 6.38 (dd, J = 7.2, 2.1 Hz, 1H) ppm 16a 1.55 411.17 17a 1.83 459.3(DMSO-d₆) δ 11.28 (s, 1H), 10.63 (s, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.86(dd, J = 8.7, 2.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.54-7.43 (m, 1H),7.43-7.34 (m, 1H), 7.34-7.28 (m, 2H), 7.05 (d, J = 8.7 Hz, 1H), 6.75 (d,J = 2.0 Hz, 1H), 6.38 (dd, J = 7.2, 2.1 Hz, 1H) ppm 18  1.39 503.4(DMSO-d₆) δ 10.70 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.83 (dd, J = 8.8,2.4 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.35-7.23 (m, 4H), 7.00 (d, J =8.7 Hz, 1H), 6.91 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 7.6, 2.3 Hz, 1H),5.53 (d, J = 9.7 Hz, 2H) ppm 18a 1.72 393.1 (DMSO-d₆) δ 11.40 (s, 1H),10.64 (s, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.8, 2.3 Hz, 1H),7.30 (tdd, J = 6.9, 5.9, 3.4 Hz, 5H), 6.99 (d, J = 8.8 Hz, 1H), 6.82 (d,J = 1.8 Hz, 1H), 6.43 (dd, J = 7.2, 2.0 Hz, 1H) ppm

Example 16

Assays for Detecting and Measuring Na_(V) Inhibition Properties ofCompounds

E-VIPR Optical Membrane Potential Assay Method with ElectricalStimulation

Sodium channels are voltage-dependent proteins that can be activated byinducing membrane voltage changes by applying electric fields. Theelectrical stimulation instrument and methods of use are described inIon Channel Assay Methods PCT/US01/21652, herein incorporated byreference and are referred to as E-VIPR. The instrument comprises amicrotiter plate handler, an optical system for exciting the coumarindye while simultaneously recording the coumarin and oxonol emissions, awaveform generator, a current- or voltage-controlled amplifier, and adevice for inserting electrodes in well. Under integrated computercontrol, this instrument passes user-programmed electrical stimulusprotocols to cells within the wells of the microtiter plate. The E-VIPRassay is conducted according to the following procedure (includingreagents and solutions, assay protocol, and data analysis). Forsimplicity, the procedure is described in the past tense, but it will beunderstood that this procedure applies to such assays conducted in thepast (if any) and to such assays conducted in the future (if any).

24 hours before the assay on E-VIPR, HEK cells expressing human NaV1.8were seeded in 384-well poly-lysine coated plates at 15,000-20,000 cellsper well. HEK cells were grown in media (exact composition is specificto each cell type and NaV subtype) supplemented with 10% FBS (FetalBovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep(Penicillin-Streptomycin; GibcoBRL #15140-122). Cells were grown invented cap flasks, in 90% humidity and 5% CO₂.

Reagents and Solutions

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

Compound Plates: 384-well round bottom plate, e.g. Corning 384-wellPolypropylene Round Bottom #3656

Cell Plates: 384-well tissue culture treated plate, e.g. Greiner#781091-1B

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Bath1 buffer: Glucose 10 mM (1.8 g/L), Magnesium Chloride (Anhydrous), 1mM (0.095 g/L), Calcium Chloride, 2 mM (0.222 g/L), HEPES 10 mM (2.38g/L), Potassium Chloride, 4.5 mM (0.335 g/L), Sodium Chloride 160 mM(9.35 g/L).

Hexyl Dye Solution: Bath1 Buffer+0.5% β-cyclodextrin (made this prior touse, Sigma #C4767), 8 μM CC2-DMPE+2.5 μM DiSBAC₆(3). To make thesolution added volume of 10% Pluronic F127 stock equal to volumes ofCC2-DMPE+DiSBAC₆(3). The order of preparation was first mixing Pluronicand CC2-DMPE, then adding DiSBAC₆(3) while vortexing, then addingBath1+β-Cyclodextrin.

Assay Protocol

1) Pre-spotted compounds (in neat DMSO) into compound plates. Vehiclecontrol (neat DMSO), the positive control (20 mM DMSO stock tetracaine,125 μM final in assay) and test compounds were added to each well at160× desired final concentration in neat DMSO. Final compound platevolume was 80 μL (80-fold intermediate dilution from 1 μL DMSO spot;160-fold final dilution after transfer to cell plate). Final DMSOconcentration for all wells in assay was 0.625%.

2) Prepared Hexyl Dye Solution.

3) Prepared cell plates. On the day of the assay, medium was aspiratedand cells were washed three times with 100 μL of Bath1 Solution,maintaining 25 μL residual volume in each well.

4) Dispensed 25 μL per well of Hexyl Dye Solution into cell plates.Incubated for 20-35 minutes at room temp or ambient conditions.

5) Dispensed 80 μL per well of Bath1 into compound plates. AcidYellow-17 (1 mM) was added and Potassium Chloride was altered from 4.5to 20 mM depending on the NaV subtype and assay sensitivity.

6) Washed cell plates three times with 100 μL per well of Bath1, leaving25 μL of residual volume. Then transferred 25 μL per well from CompoundPlates to Cell Plates. Incubated for 20-35 minutes at room temp/ambientcondition.

7) Read Plate on E-VIPR. Used the current-controlled amplifier todeliver stimulation wave pulses for 10 seconds and a scan rate of 200Hz. A pre-stimulus recording was performed for 0.5 seconds to obtain theun-stimulated intensities baseline. The stimulatory waveform wasfollowed by 0.5 seconds of post-stimulation recording to examine therelaxation to the resting state.

Data Analysis

Data was analyzed and reported as normalized ratios of emissionintensities measured in the 460 nm and 580 nm channels. The response asa function of time was reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{\;_{460\mspace{14mu}{nm}}} - {background}_{\;_{460\mspace{14mu}{nm}}}} \right)}{\left( {{intensity}_{\;_{580\mspace{14mu}{nm}}} - {background}_{\;_{580\mspace{14mu}{nm}}}} \right)}$

The data was further reduced by calculating the initial (R_(i)) andfinal (R_(f)) ratios. These were the average ratio values during part orall of the pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R□□=R_(f)/R_(i) wasthen calculated and reported as a function of time.

Control responses were obtained by performing assays in the presence ofa compound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls werecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound

Example 17

Electrophysiology Assays for Na_(V) Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)were visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modewas used to assess the compound's IC₅₀ holding the cells at −60 mV. Inaddition, the “current clamp” mode was employed to test the efficacy ofthe compounds in blocking action potential generation in response tocurrent injections. The results of these experiments contributed to thedefinition of the efficacy profile of the compounds.

Selected compounds and intermediates of the present invention herein areactive against Na_(V)1.8 sodium channels as measured using the assaysdescribed herein and as presented in Table 4 below.

TABLE 4 Na_(v)1.8 IC₅₀ activity Cmpd. Na_(v)1.8 IC₅₀ No (μM) 1 0.004  1a0.001 2 0.028  2a 0.003  3a 0.006  4a 0.011  5a 0.011  6a 0.012  7a0.013  8a 0.013 9 0.33  9a 0.014 10  0.086 10a 0.017 11a 0.028 12a 0.0313  0.329 13a 0.03 14a 0.037 15a 0.044 16a 0.05 17a 0.051 18  0.457 18a0.054

Example 18

IonWorks Assays.

This assay is performed to determine the activity for the compounds ofthe present invention against non Na_(V)1.8 channels. This assay isconducted according to the following procedure. For simplicity, theprocedure is described in the past tense, but it will be understood thatthis procedure applies to such assays conducted in the past (if any) andto such assays conducted in the future (if any). Sodium currents wererecorded using the automated patch clamp system, IonWorks (MolecularDevices Corporation, Inc.). Cells expressing Na_(V) subtypes wereharvested from tissue culture and placed in suspension at 0.5-4 millioncells per mL Bath1. The IonWorks instrument measured changes in sodiumcurrents in response to applied voltage clamp similarly to thetraditional patch clamp assay, except in a 384-well format. Using theIonWorks, dose-response relationships were determined in voltage clampmode by depolarizing the cell from the experiment specific holdingpotential to a test potential of about 0 mV before and followingaddition of the test compound. The influence of the compound on currentswere measured at the test potential.

Example 19

Aqueous Solubility Study

The aqueous solubility of compound 9 and 9a were determined according tothe following procedure. Solubility data was determined at ambientconditions by equilibrating the compound with water on a shaking bed for24 hours, followed by centrifugation and separation of the saturatedsolutions. The pH value of each media was measured beforecentrifugation, and the saturated solutions were assayed by HPLC. Theaqueous solubility of compound 9a in water was low (<0.001 mg/ml at pH6.0) whereas the aqueous solubility of compound 9 in water wasapproximately 0.3 mg/ml.

TABLE 5 Aqueous Solubility of Compounds 9 and 9a: Compound Solid form pHSolubility (mg/mL)  9a crystalline 6.0 <0.001  9a crystalline 1.2 <0.0019 crystalline 1 0.002 9 crystalline 3 0.11 9 crystalline 3.3 0.24 9crystalline 5 0.42 9 crystalline 7 0.50 9 crystalline 8 2.24

Example 20

Pharmacokinetic Studies

The pharmacokinetic parameters of selected compounds of this inventionwere determined in the experiments described below. General analyticprocedures and specific experimental protocols were employed as follows:

General Analytic Procedures

The following general analytic procedures were employed in thepharmacokinetic experiments described below:

Sample Analysis.

Concentrations of compound 9 and compound 9a in plasma were determinedusing a high performance liquid chromatography/tandem mass spectrometry(HPLC/MS/MS) method. Before extraction, plasma samples were dilutedusing blank plasma at an appropriate dilution factor, as necessary,depending on the dose level. Compound 9a and compound 9 along with theinternal standard (IS) were extracted from (diluted) plasma, 20 μL each,by direct protein precipitation with acetonitrile (1:25 ratio ofplasma/acetonitrile). After centrifugation, the supernatant extract (10μL) was injected onto the LC/MS/MS system. The HPLC system included aPhenomenex Synergy Kinetix C8 column, 2.6 micron, 2.0 mm diameter×75 mmlong eluted with a gradient mobile phase consisting of 0.1% formic acidin water or in acetonitrile.

The analytes were detected by MS/MS with Electrospray Ionization (ESI)in the mode of multiple reaction monitoring (MRM). The lower limit ofquantitation (LLOQ) was 1 to 10 ng/mL for compound 9a and 2.5 to 25ng/mL for compound 9. The linear range of the assay was from 1 or 10 to10000 ng/mL for compound 9a and 2.5 or 25 to 10000 ng/mL for compound 9.The intra-day and inter-day assay accuracy was within 20% of the nominalvalues. The intra- and inter-day assay variability was ≤20%.

Pharmacokinetic Data Analysis.

Plasma concentration-time profiles of compound 9a and compound 9 wereanalyzed by noncompartmental pharmacokinetic methods using Watson LIMSversion 7.4 SP3 (Thermo Fisher Scientific, Inc., Philadelphia, Pa.)

Key pharmacokinetic parameters such as AUC_(all), AUC_(extra), C_(max),t_(max), Cl, Vss and t_(1/2) were determined.

Statistical Data Analysis.

Descriptive statistical data of pharmacokinetic parameters werecalculated, including the mean, standard deviation (SD), using WatsonLIMS version 7.4 SP3 or Microsoft Excel 2000.

Monkey Oral Study

Male or female cynomolgus monkeys (n=3 per dose group) were administeredsingle nominal PO doses of 10, 40, 100, 300, 500, 750 and 1000 mg/kg ofcompound 9 by gavage. Compound 9 was formulated in 30% PEG400 and 10%TPGS in water or 5% TPGS, 5% PVP-K30 in 50 mM Citrate, pH 5. Animalswere fasted overnight prior to dosing, and were fed two hours post dose.Water was available before and after dosing.

Blood samples (approximately 0.25 mL each) were collected via a carotidartery catheter prior to dosing and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48and 72 hours post dose. Each blood sample was collected into a tube thatwas kept on wet ice and contained potassium EDTA as the anticoagulant.Plasma was separated and stored at approximately −70° C. until analysis.

Plasma samples were analyzed using a liquid chromatography/tandem massspectrometry (LC/MS/MS) method to determine the concentrations ofcompound 9a and compound 9 with a lower limit of quantitation (LLOQ) of1.00 to 10.0 ng/mL for compound 9a, and 10.0 to 25.0 ng/mL for compound9. Plasma concentration vs. time data of compound 9a was subjected tononcompartmental pharmacokinetic (PK) analysis. The results of thisanalysis are provided in Table 7. For compound 9, plasma concentrationswere below LLOQ for the majority of the samples, and no PK analysiscould be performed.

TABLE 7 Pharmacokinetic Data from Monkey Oral Study Nominal DoseAUC_(extra) C_(max) T_(max) T_(1/2) (mg/kg) Formulation Analyte (μg ·hr/mL) (μg/mL) (hr) (hr) 10 30% PEG400/10% TPGS/60% water Cmpd 21.5 ±13.7 1.13 ± 0.187 4.67 ± 3.06 8.57 ± 2.75 9a 40 5% TPGS/5% PVP- Cmpd62.4 ± 23.8 4.50 ± 0.51 3.33 ± 1.15 9.58 ± 3.91 K30/50 mMCitrate pH5 9a100 5% TPGS/5% PVP- Cmpd 49.6 ± 10.7 3.34 ± 0.34 4.00 ± 0.00 7.04 ± 0.36K30/50 mMCitrate pH5 9a 300 5% TPGS/5% PVP- Cmpd 93.4 ± 22.7 5.77 ± 1.462.67 ± 1.15 11.6 ± 2.3 K30/50 mMCitrate pH5 9a 500 5% TPGS/5% PVP- Cmpd 124 ± 6.0 5.76 ± 1.69 6.00 ± 3.46 9.80 ± 1.08 K30/50 mMCitrate pH5 9a750 5% TPGS/5% PVP- Cmpd  138 ± 47.3 7.49 ± 3.13 6.67 ± 4.62 13.1 ± 3.1K30/50 mMCitrate pH5 9a 1000 5% TPGS/5% PVP- Cmpd  176 ± 20.7 7.88 ±0.80 4.00 ± 0.00 13.5 ± 3.1 K30/50 mMCitrate pH5 9a N = 3 monkeys perdose level, Mean ± Standard deviation

Rat Oral Study

Groups of male and female Sprague Dawley rats (n=3 per dose group) wereadministered single nominal oral doses of 10, 100, 400, 640, 1000 mg/kg(for males) and 30, 100, 300, 640, 1000 mg/kg (for females) of compound9 by gavage. Compound 9 was formulated in either 30% PEG400 and 10% TPGSin water or 5% TPGS, 5% PVP-K30 in 50 mM Citrate, pH 5. Animals had freeaccess to food and water before and after dosing. Blood samples(approximately 0.25 mL each) were collected via a carotid arterycatheter prior to dosing and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48 and 72hours post dose. Each blood sample was collected into a tube that waskept on wet ice and contained potassium EDTA as the anticoagulant.Plasma was separated and stored at approximately −70° C. until analysis.

Plasma samples were analyzed using a liquid chromatography/tandem massspectrometry (LC/MS/MS) method to determine the concentrations ofcompound 9a and compound 9 with a lower limit of quantitation (LLOQ) of1 to 25 ng/mL for compound 9a and 2.5 to 25 ng/mL for compound 9. Plasmaconcentration vs. time data of compound 9a was subjected tononcompartmental pharmacokinetic (PK) analysis. The results of thisanalysis are provided in Table 8. For compound 9, plasma concentrationswere below LLOQ for the majority of the samples, and no PK analysiscould be performed.

TABLE 8 Pharmacokinetic Data from Rat Oral Study Nominal DoseAUC_(extra) C_(max) T_(max) T_(1/2) Gender (mg/kg) Formulation Analyte(μg · hr/mL) (μg/mL) (hr) (hr) Male 10 5% TPGS/5% PVP- Cmpd 3.6 ± 0.240.29 ± 0.05 5.33 ± 2.31 3.80 ± 0.73 K30/50 mMCitrate pH5 9a 100 5%TPGS/5% PVP- Cmpd 24.8 ± 4.6 1.67 ± 0.19 8.00 ± 0.00 5.36 ± 2.37 K30/50mMCitrate pH5 9a 400 5% TPGS/5% PVP- Cmpd 68.6 ± 25.7 3.74 ± 1.25 5.67 ±4.04 5.20 ± 1.96 K30/50 mMCitrate pH5 9a 640 5% TPGS/5% PVP- Cmpd 74.9 ±24.1 4.76 ± 0.98 6.00 ± 3.46 6.91 ± 1.84 K30/50 mMCitrate pH5 9a 1000 5%TPGS/5% PVP- Cmpd 88.5 ± 41.0 4.54 ± 0.91 6.67 ± 2.31 7.95 ± 2.24 K30/50mMCitrate pH5 9a Females 30 5% TPGS/5% PVP- Cmpd 99.2 ± 6.88 3.33 ± 0.436.67 ± 2.31 10.8 ± 1.60 K30/50 mMCitrate pH5 9a 100 5% TPGS/5% PVP- Cmpd 187 ± 17.5 5.82 ± 0.58 12.0 ± 0.00 9.15 ± 0.44 K30/50 mMCitrate pH5 9a300 5% TPGS/5% PVP- Cmpd  282 ± 74.2 7.90 ± 1.30 10.7 ± 2.31 13.1 ± 2.65K30/50 mMCitrate pH5 9a 640 5% TPGS/5% PVP- Cmpd  324 ± 32.8 10.0 ± 1.459.33 ± 2.31 7.51 ± 1.86 K30/50 mMCitrate pH5 9a 1000 5% TPGS/5% PVP-Cmpd  345 ± 69.6 10.6 ± 3.58 13.3 ± 9.24 7.90 ± 3.37 K30/50 mMCitratepH5 9a N = 3 rats per dose level, Mean ± Standard deviation

Rat IV Study

Male Sprague Dawley rats (n=3) were administered a single nominal IVbolus dose of 1 mg/kg of compound 9 via a jugular vein cannula. Compound9 was formulated in DMI vehicle, consisting of 35% PEG400, 15% ethanol,10% dimethyl isosorbide and 40% of (5% dextran in water). Animals hadfree access to food and water before and after dosing. Blood samples(approximately 0.25 mL each) were collected via a carotid arterycatheter prior to dosing and at 5 min, 10 min, 0.25, 0.5, 1, 2, 4, 8,12, 24 hours post dose. Each blood sample was collected into a tube thatwas kept on wet ice and contained potassium EDTA as the anticoagulant.Plasma was separated and stored at approximately −70° C. until analysis.

Plasma samples were analyzed using a liquid chromatography/tandem massspectrometry (LC/MS/MS) method to determine the concentrations ofcompound 9a and compound 9 with a lower limit of quantitation (LLOQ) of1 ng/mL for compound 9a and 2.5 ng/mL for compound 9. Plasmaconcentration vs. time data were subjected to noncompartmentalpharmacokinetic (PK) analysis. The results of this analysis are providedin Table 9. For compound 9, plasma concentrations were below LLOQ forthe majority of the samples, and no PK analysis could be performed.

TABLE 9 Pharmacokinetic Data from Rat IV Study Dose C0 AUC_(all)AUC_(extra) t½ Cl Vss (mg/kg) Formulation Analyte (μg/ml) (μg * hr/ml)(μg * hr/ml) (hr) (ml/min/kg) (L/kg) 1 DMI Cmpd 0.259 0.592 0.611 2.4318.7 3.77 9a

The studies described above, demonstrate that compound 9 is converted invivo into compound 9a in at least rats and monkeys.

Many modifications and variations of the embodiments described hereinmay be made without departing from the scope, as is apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only.

We claim:
 1. A compound selected from the group consisting of:


2. A method of inhibiting a voltage-gated sodium channel in a subjectcomprising administering to the subject a compound according to claim 1.3. The method of claim 2, wherein the voltage-gated sodium channel isNa_(V)1.8.
 4. The method of claim 2, wherein the compound is:


5. The method of claim 4, wherein the voltage-gated sodium channel isNa_(V)1.8.
 6. The method of claim 2, wherein the compound is:


7. The method of claim 6, wherein the voltage-gated sodium channel isNa_(V)1.8.
 8. A method of treating or lessening the severity in asubject of chronic pain, gut pain, neuropathic pain, musculoskeletalpain, acute pain, inflammatory pain, cancer pain, idiopathic pain,postsurgical pain, visceral pain, multiple sclerosis,Charcot-Marie-Tooth syndrome, incontinence, pathological cough, orcardiac arrhythmia comprising administering to the subject an effectiveamount of a compound according to claim
 1. 9. The method of claim 8,wherein the compound is:


10. The method of claim 9, wherein the method comprises treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.
 11. The method of claim 9, wherein themethod comprises treating or lessening the severity in a subject ofneuropathic pain.
 12. The method of claim 11, wherein neuropathic paincomprises trigeminal neuralgia.
 13. The method of claim 11, whereinneuropathic pain comprises idiopathic small-fiber neuropathy.
 14. Themethod of claim 11, wherein neuropathic pain comprises postherpeticneuralgia.
 15. The method of claim 9, wherein the method comprisestreating or lessening the severity in a subject of musculoskeletal pain.16. The method of claim 15, wherein musculoskeletal pain comprisesosteoarthritis pain.
 17. The method of claim 9, wherein the methodcomprises treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain.
 18. The method of claim 9, wherein the method comprisestreating or lessening the severity in a subject of idiopathic pain,wherein idiopathic pain comprises fibromyalgia pain.
 19. The method ofclaim 9, wherein the method comprises treating or lessening the severityin a subject of acute pain.
 20. The method of claim 19, wherein acutepain comprises acute post-operative pain.
 21. The method of claim 9,wherein the method comprises treating or lessening the severity in asubject of postsurgical pain.
 22. The method of claim 9, wherein themethod comprises treating or lessening the severity in a subject ofvisceral pain.
 23. The method according to claim 9, wherein said subjectis treated with one or more additional therapeutic agents administeredconcurrently with, prior to, or subsequent to treatment with thecompound.
 24. The method of claim 8, wherein the compound is:


25. The method of claim 24, wherein the method comprises treating orlessening the severity in a subject of gut pain, wherein gut paincomprises inflammatory bowel disease pain, Crohn's disease pain orinterstitial cystitis pain.
 26. The method of claim 24, wherein themethod comprises treating or lessening the severity in a subject ofneuropathic pain.
 27. The method of claim 26, wherein neuropathic paincomprises trigeminal neuralgia.
 28. The method of claim 26, whereinneuropathic pain comprises idiopathic small-fiber neuropathy.
 29. Themethod of claim 26, wherein neuropathic pain comprises postherpeticneuralgia.
 30. The method of claim 24, wherein the method comprisestreating or lessening the severity in a subject of musculoskeletal pain.31. The method of claim 30, wherein musculoskeletal pain comprisesosteoarthritis pain.
 32. The method of claim 24, wherein the methodcomprises treating or lessening the severity in a subject ofinflammatory pain, wherein inflammatory pain comprises rheumatoidarthritis pain.
 33. The method of claim 24, wherein the method comprisestreating or lessening the severity in a subject of idiopathic pain,wherein idiopathic pain comprises fibromyalgia pain.
 34. The method ofclaim 24, wherein the method comprises treating or lessening theseverity in a subject of acute pain.
 35. The method of claim 34, whereinacute pain comprises acute post-operative pain.
 36. The method of claim24, wherein the method comprises treating or lessening the severity in asubject of postsurgical pain.
 37. The method of claim 24, wherein themethod comprises treating or lessening the severity in a subject ofvisceral pain.
 38. The method according to claim 24, wherein saidsubject is treated with one or more additional therapeutic agentsadministered concurrently with, prior to, or subsequent to treatmentwith the compound.